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Extra-renal manifestations of atypical hemolytic uremic syndrome

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Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare and complex disease resulting from abnormal alternative complement activation with a wide range of clinical presentations. Extra-renal manifestations of aHUS can involve many organ systems, including the peripheral and central nervous, gastrointestinal, cardiovascular, integumentary, pulmonary, as well as the eye. While some of these extra-renal manifestations occur in the acute phase of aHUS, some can also occur as long-term sequelae of unopposed complement activation. Extra-renal symptoms are observed in approximately 20% of patients with aHUS, with the incidence of specific organ system complications ranging from a few case reports to 50% of described patients. Careful monitoring for extra-renal involvement is critical in patients with aHUS, as prompt evaluation and management may decrease the risk of high morbidity and mortality associated with aHUS.

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References

  1. Ohanian M, Cable C, Halka K (2011) Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome. Clin Pharmacol 3:5–12

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Talarico V, Aloe M, Monzani A, Miniero R, Bona G (2016) Hemolytic uremic syndrome in children. Minerva Pediatr 68:441–455

    PubMed  Google Scholar 

  3. Taylor CM, Machin S, Wigmore SJ, Goodship TH, working party from the Renal Association tBCfSiH, the British Transplantation S (2010) Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37–47

    Article  CAS  PubMed  Google Scholar 

  4. Geerdink LM, Westra D, van Wijk JA, Dorresteijn EM, Lilien MR, Davin JC, Komhoff M, Van Hoeck K, van der Vlugt A, van den Heuvel LP, van de Kar NC (2012) Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatr Nephrol 27:1283–1291

    Article  PubMed  PubMed Central  Google Scholar 

  5. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschenes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, Smith RJ (2014) Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 25:55–64

    Article  CAS  PubMed  Google Scholar 

  8. Hindmarsh EJ, Marks RM (1998) Complement activation occurs on subendothelial extracellular matrix in vitro and is initiated by retraction or removal of overlying endothelial cells. J Immunol 160:6128–6136

    CAS  PubMed  Google Scholar 

  9. Cataland SR, Wu HM (2014) How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 123:2478–2484

    Article  CAS  PubMed  Google Scholar 

  10. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 111:1181–1190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, Rafail S, Kartalis G, Sideras P, Lambris JD (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 177:4794–4802

    Article  CAS  PubMed  Google Scholar 

  12. Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622–633

    Article  CAS  PubMed  Google Scholar 

  13. Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, Bedrosian CL, Faas SJ (2015) Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood 125:3253–3262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687

    Article  CAS  PubMed  Google Scholar 

  15. Hofer J, Rosales A, Fischer C, Giner T (2014) Extra-renal manifestations of complement-mediated thrombotic microangiopathies. Front Pediatr 2:97

    Article  PubMed  PubMed Central  Google Scholar 

  16. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Fremeaux-Bacchi V, International HUS (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31:15–39

    Article  PubMed  Google Scholar 

  17. Loirat C, Fremeaux-Bacchi V (2011) Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, Andre JL, Takagi N, Cheong HI, Hari P, Le Quintrec M, Niaudet P, Loirat C, Fridman WH, Fremeaux-Bacchi V (2010) Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 21:2180–2187

    Article  PubMed  PubMed Central  Google Scholar 

  19. Besbas N, Gulhan B, Soylemezoglu O, Ozcakar ZB, Korkmaz E, Hayran M, Ozaltin F (2017) Turkish pediatric atypical hemolytic uremic syndrome registry: initial analysis of 146 patients. BMC Nephrol 18:6

    Article  PubMed  PubMed Central  Google Scholar 

  20. Brocklebank V, Johnson S, Sheerin TP, Marks SD, Gilbert RD, Tyerman K, Kinoshita M, Awan A, Kaur A, Webb N, Hegde S, Finlay E, Fitzpatrick M, Walsh PR, Wong EKS, Booth C, Kerecuk L, Salama AD, Almond M, Inward C, Goodship TH, Sheerin NS, Marchbank KJ, Kavanagh D (2017) Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland. Kidney Int 92:1261–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shiari R, Parvaneh VJ, Dalirani R, Farivar S, Shiva MR (2014) Atypical hemolytic-uremic syndrome associated with antiphospholipid antibodies and antiphospholipid syndrome; a novel presentation. Pediatric Rheumatology 12:P363

    Article  PubMed Central  Google Scholar 

  22. Neuhaus TJ, Calonder S, Leumann EP (1997) Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child 76:518–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, Karpman D, Landau D, Langman C, Licht C, Pecoraro C, Riedl M, Siomou E, van de Kar N, Walle JV, Loirat C, Taylor CM (2014) An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol 29:1967–1978

    Article  PubMed  Google Scholar 

  24. Fidan K, Goknar N, Gulhan B, Melek E, Yildirim ZY, Baskin E, Hayran M, Gulleroglu K, Ozcakar ZB, Ozaltin F, Soylemezoglu O (2018) Extra-Renal manifestations of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 33:1395–1403

    Article  PubMed  Google Scholar 

  25. Diamante Chiodini B, Davin JC, Corazza F, Khaldi K, Dahan K, Ismaili K, Adams B (2014) Eculizumab in anti-factor h antibodies associated with atypical hemolytic uremic syndrome. Pediatrics 133:e1764–e1768

    Article  PubMed  Google Scholar 

  26. Gulleroglu K, Fidan K, Hancer VS, Bayrakci U, Baskin E, Soylemezoglu O (2013) Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. Pediatr Nephrol 28:827–830

    Article  PubMed  Google Scholar 

  27. Salem G, Flynn JM, Cataland SR (2013) Profound neurological injury in a patient with atypical hemolytic uremic syndrome. Ann Hematol 92:557–558

    Article  PubMed  Google Scholar 

  28. Koehl B, Boyer O, Biebuyck-Gouge N, Kossorotoff M, Fremeaux-Bacchi V, Boddaert N, Niaudet P (2010) Neurological involvement in a child with atypical hemolytic uremic syndrome. Pediatr Nephrol 25:2539–2542

    Article  PubMed  Google Scholar 

  29. Tsai HM, Kuo E (2014) Eculizumab therapy leads to rapid resolution of thrombocytopenia in atypical hemolytic uremic syndrome. Adv Hematol 2014:295323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Noris M, Remuzzi G (2014) Cardiovascular complications in atypical haemolytic uraemic syndrome. Nat Rev Nephrol 10:174–180

    Article  PubMed  Google Scholar 

  31. Vilalta R, Lara E, Madrid A, Chocron S, Munoz M, Casquero A, Nieto J (2012) Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome. Pediatr Nephrol 27:2323–2326

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sallee M, Daniel L, Piercecchi MD, Jaubert D, Fremeaux-Bacchi V, Berland Y, Burtey S (2010) Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol Dial Transplant 25:2028–2032

    Article  PubMed  Google Scholar 

  33. Hu H, Nagra A, Haq MR, Gilbert RD (2014) Eculizumab in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvement. Pediatr Nephrol 29:1103–1106

    Article  PubMed  Google Scholar 

  34. Loirat C, Macher MA, Elmaleh-Berges M, Kwon T, Deschenes G, Goodship TH, Majoie C, Davin JC, Blanc R, Savatovsky J, Moret J, Fremeaux-Bacchi V (2010) Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation. Nephrol Dial Transplant 25:3421–3425

    Article  PubMed  Google Scholar 

  35. Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T (2010) Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis 55:708–711

    Article  PubMed  Google Scholar 

  36. Vergouwen MD, Adriani KS, Roos YB, Groothoff JW, Majoie CB (2008) Proximal cerebral artery stenosis in a patient with hemolytic uremic syndrome. AJNR Am J Neuroradiol 29:e34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Davin JC, Majoie C, Groothoff J, Gracchi V, Bouts A, Goodship TH, Loirat C (2011) Prevention of large-vessel stenoses in atypical hemolytic uremic syndrome associated with complement dysregulation. Pediatr Nephrol 26:155–157

    Article  PubMed  Google Scholar 

  38. Bekassy ZD, Kristoffersson AC, Cronqvist M, Roumenina LT, Rybkine T, Vergoz L, Hue C, Fremeaux-Bacchi V, Karpman D (2013) Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions. Nephrol Dial Transplant 28:2899–2907

    Article  CAS  PubMed  Google Scholar 

  39. Bhatti NK, Karimi Galougahi K, Paz Y, Nazif T, Moses JW, Leon MB, Stone GW, Kirtane AJ, Karmpaliotis D, Bokhari S, Hardy MA, Dube G, Mohan S, Ratner LE, Cohen DJ, Ali ZA (2016) Diagnosis and management of cardiovascular disease in Advanced and End-Stage Renal Disease. J Am Heart Assoc https://doi.org/10.1161/JAHA.116.003648.

  40. Mallett A, Hughes P, Szer J, Tuckfield A, Van Eps C, Cambell SB, Hawley C, Burke J, Kausman J, Hewitt I, Parnham A, Ford S, Isbel N (2015) Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort. Intern Med J 45:1054–1065

    Article  CAS  PubMed  Google Scholar 

  41. Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, Chatelet V, Mousson C, Mourad G, Bridoux F, Cassuto E, Loirat C, Rondeau E, Delahousse M, Fremeaux-Bacchi V (2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 13:663–675

    Article  CAS  PubMed  Google Scholar 

  42. Roumenina LT, Frimat M, Miller EC, Provot F, Dragon-Durey MA, Bordereau P, Bigot S, Hue C, Satchell SC, Mathieson PW, Mousson C, Noel C, Sautes-Fridman C, Halbwachs-Mecarelli L, Atkinson JP, Lionet A, Fremeaux-Bacchi V (2012) A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood 119:4182–4191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ozel A, Caliskan U, Gucer S (2003) Peripheral gangrene complicating hemolytic uremic syndrome in a child. Pediatr Nephrol 18:465–467

    PubMed  Google Scholar 

  44. Ardissino G, Tel F, Testa S, Marzano AV, Lazzari R, Salardi S, Edefonti A (2014) Skin involvement in atypical hemolytic uremic syndrome. Am J Kidney Dis 63:652–655

    Article  PubMed  Google Scholar 

  45. Kaplan BS, Garcia CD, Chesney RW, Segar WE, Giugno K, Chem R (2000) Peripheral gangrene complicating idiopathic and recessive hemolytic uremic syndromes. Pediatr Nephrol 14:985–989

    Article  CAS  PubMed  Google Scholar 

  46. Malina M, Gulati A, Bagga A, Majid MA, Simkova E, Schaefer F (2013) Peripheral gangrene in children with atypical hemolytic uremic syndrome. Pediatrics 131:e331–e335

    Article  PubMed  Google Scholar 

  47. Sturm V, Menke MN, Landau K, Laube GF, Neuhaus TJ (2010) Ocular involvement in paediatric haemolytic uraemic syndrome. Acta Ophthalmol 88:804–807

    Article  PubMed  Google Scholar 

  48. Zheng X, Gorovoy IR, Mao J, Jin J, Chen X, Cui QN (2014) Recurrent ocular involvement in pediatric atypical hemolytic uremic syndrome. J Pediatr Ophthalmol Strabismus 51:e62–e65

    PubMed  Google Scholar 

  49. Greenwood GT (2015) Case report of atypical hemolytic uremic syndrome with retinal arterial and venous occlusion treated with eculizumab. Int Med Case Rep J 8:235–239

    Article  PubMed  PubMed Central  Google Scholar 

  50. Larakeb A, Leroy S, Fremeaux-Bacchi V, Montchilova M, Pelosse B, Dunand O, Deschenes G, Bensman A, Ulinski T (2007) Ocular involvement in hemolytic uremic syndrome due to factor H deficiency--are there therapeutic consequences? Pediatr Nephrol 22:1967–1970

    Article  PubMed  Google Scholar 

  51. Ramos de Carvalho JE, Schlingemann RO, Oranje M, Bemelman FJ, van Schooneveld MJ (2017) Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome. Int Ophthalmol 38:399–407

    PubMed  PubMed Central  Google Scholar 

  52. Berger BE (2016) The Alternative Pathway of Complement and the Evolving Clinical-Pathophysiological spectrum of Atypical Hemolytic Uremic Syndrome. Am J Med Sci 352:177–190

    Article  PubMed  Google Scholar 

  53. De Yao J, Kaplan R, Magro C (2015) An Atypical Case of Atypical Hemolytic Uremic Syndrome: Predominant Gastrointestinal Involvement, Intact Renal Function, and C5b-9 Deposition in colon and skin. J Hematol 4:193–195

    Article  Google Scholar 

  54. Webb TN, Griffiths H, Miyashita Y, Bhatt R, Jaffe R, Moritz M, Hofer J, Swiatecka-Urban A (2015) Atypical Hemolytic Uremic Syndrome and Chronic Ulcerative Colitis Treated with eculizumab. Int J Med Pharm Case Reports 4:105–112

    Article  PubMed  PubMed Central  Google Scholar 

  55. Green H, Harari E, Davidovits M, Blickstein D, Grossman A, Gafter U, Gafter-Gvili A (2014) Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab. Ren Fail 36:1119–1121

    Article  CAS  PubMed  Google Scholar 

  56. Roman-Ortiz E, Mendizabal Oteiza S, Pinto S, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2014) Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene. Pediatr Nephrol 29:149–153

    Article  PubMed  Google Scholar 

  57. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C, French Society of Pediatric N (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400

    Article  CAS  PubMed  Google Scholar 

  58. Borowitz MJ, Craig FE, Digiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, Wittwer CT, Richards SJ, Clinical Cytometry S (2010) Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 78:211–230

    PubMed  Google Scholar 

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  1. Department of Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Cassandra Formeck & Agnieszka Swiatecka-Urban

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  1. Cassandra Formeck
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  2. Agnieszka Swiatecka-Urban
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Correspondence to Cassandra Formeck.

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Dr. Cassandra Formeck - funded by NIDDK T32 training grant.

Dr. Agnieszka Swiatecka-Urban - funded by NIH grant R56HL127202.

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The authors declare that they have no conflict of interest.

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Answers to the Questions:

1. b; 2. d; 3. b; 4. e; 5. e

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Formeck, C., Swiatecka-Urban, A. Extra-renal manifestations of atypical hemolytic uremic syndrome. Pediatr Nephrol 34, 1337–1348 (2019). https://doi.org/10.1007/s00467-018-4039-7

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