Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지

Hemolytic uremic syndrome

용혈성 요독 증후군

  • 박혜원 (포천중문의대 소아과학교실)
  • Received : 2007.08.23
  • Accepted : 2007.09.13
  • Published : 2007.10.15
Download PDF
⟨ Previous Next ⟩

Abstract

The hemolytic uremic syndrome (HUS) is a rare disease of microangiopathic hemolytic anemia, low platelet count and renal impairment. HUS usually occurs in young children after hemorrhagic colitis by shigatoxin-producing enterohemorrhagic E. coli (D+HUS). HUS is the most common cause of acute renal failure in infants and young children, and is a substantial cause of acute mortality and morbidity; however, renal function recovers in most of them. About 10% of children with HUS do not reveal preceding diarrheal illness, and is referred to as D- HUS or atypical HUS. Atypical HUS comprises a heterogeneous group of thrombomicroangiopathy (TMA) triggered by non-enteric infection, virus, drug, malignancies, transplantation, and other underlying medical condition. Emerging data indicate dysregulation of alternative complement pathway in atypical HUS, and genetic analyses have identified mutations of several regulatory genes; i.e. the fluid phase complement regulator Factor H (CFH), the integral membrane regulator membrane cofactor protein (MCP; CD46) and the serine protease Factor I (IF). The uncontrolled activation of the complement alternative pathway results in the excessive consumption of C3. Plasma exchange or plasma infusion is recommended for treatment of, and has dropped the mortality rate. However, overall prognosis is poor, and many patients succumb to end-stage renal disease. Clinical presentations, response to plasma therapy, and outcome after renal transplantation are influenced by the genotype of the complement regulators. Thrombotic thrombocytopenic purpura (TTP), another type of TMA, occurs mainly in adults as an acquired disease accompanied by fever, neurologic deficits and renal abnormalities. However, less frequent cases of congenital or hereditary TTP associated with ADAMTS-13 (a disintegrin and metalloprotease, with thrombospondin 1-like domains 13) gene mutations have been reported, also. Recent advances in molecular genetics better allow various HUS to be distinguished on the basis of their pathogenesis. The genetic analysis of HUS is important in defining the underlying etiology, predicting the genotype-related outcome and optimizing the management of the patients.

Keywords

References

  1. Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr 2005;17: 200-4 https://doi.org/10.1097/01.mop.0000152997.66070.e9
  2. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005;16:1035-50 https://doi.org/10.1681/ASN.2004100861
  3. Morris BH, Miller-Loncar CL, Landry SH, Smith KE, Swank PR, Denson SE. Feeding, medical factors, and developmental outcome in premature infants. Clin Pediatr(Phila) 1999;38: 451-7 https://doi.org/10.1177/000992289903800802
  4. Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 2006;70:423-31 https://doi.org/10.1038/sj.ki.5001581
  5. Loirat C, Taylor CM. Hemolytic uremic syndorome. In: Avner ED, Harmon WE, Niaudet P, editors. Pediatric Nephrology. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2004. p. 887-915
  6. Inward CD, Howie AJ, Fitzpatrick MM, Rafaat F, Milford DV, Taylor CM. Renal histopathology in fatal cases of diarrhoea-associated haemolytic uraemic syndrome. british association for paediatric nephrology. Pediatr Nephrol 1997; 11:556-9 https://doi.org/10.1007/s004670050337
  7. Taylor CM, Chua C, Howie AJ, Risdon RA, British Association for Paediatric Nephrology. Clinico-pathological findings in diarrhoea-negative haemolytic uraemic syndrome. Pediatr Nephrol 2004;19:419-25 https://doi.org/10.1007/s00467-003-1385-9
  8. Karmali MA, Steele BT, Petrie M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing escherichia coli in stools. Lancet 1983 Mar 19;1(8325):619-20
  9. Riley LW, Remis RS, Helgerson SD, McGee HB, Wells JG, Davis BR, et al. Hemorrhagic colitis associated with a rare escherichia coli serotype. N Engl J Med 1983 24;308:681-5
  10. Tarr PI, Hickman RO. Hemolytic uremic syndrome epidemiology: A population-based study in king county, washington, 1971 to 1980. Pediatrics. 1987 Jul;80(1):41-5
  11. Rowe PC, Orrbine E, Wells GA, McLaine PN. Epidemiology of hemolytic-uremic syndrome in canadian children from 1986 to 1988. the canadian pediatric kidney disease reference centre. J Pediatr. 1991;119:218-24 https://doi.org/10.1016/S0022-3476(05)80730-9
  12. Siegler RL, Pavia AT, Christofferson RD, Milligan MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in utah. Pediatrics 1994;94:35-40
  13. Bonnet R, Souweine B, Gauthier G, Rich C, Livrelli V, Sirot J, et al. Non-O157:H7 Stx2-producing escherichia coli strains associated with sporadic cases of hemolytic-uremic syndrome in adults. J Clin Microbiol 1998;36:1777-80
  14. Srivastava RN, Moudgil A, Bagga A, Vasudev AS. Hemolytic uremic syndrome in children in northern india. Pediatr Nephrol 1991;5:284-8 https://doi.org/10.1007/BF00867477
  15. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing escherichia coli and haemolytic uraemic syndrome. Lancet 2005 19-25;365:1073-86
  16. Lopez EL, Contrini MM, Devoto S, de Rosa MF, Grana MG, Aversa L, et al. Incomplete hemolytic-uremic syndrome in argentinean children with bloody diarrhea. J Pediatr 1995; 127:364-7 https://doi.org/10.1016/S0022-3476(95)70064-1
  17. Karch H, Tarr PI, Bielaszewska M. Enterohaemorrhagic escherichia coli in human medicine. Int J Med Microbiol 2005;295:405-18 https://doi.org/10.1016/j.ijmm.2005.06.009
  18. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002 22;347:589-600 https://doi.org/10.1056/NEJMra020528
  19. Karmali MA. Infection by shiga toxin-producing escherichia coli: An overview. Mol Biotechnol 2004;26:117-22 https://doi.org/10.1385/MB:26:2:117
  20. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of escherichia coli O157:H7 infections. N Engl J Med 2000 29;342:1930-6 https://doi.org/10.1056/NEJM200006293422601
  21. Grif K, Dierich MP, Karch H, Allerberger F. Strain-specific differences in the amount of shiga toxin released from enterohemorrhagic escherichia coli O157 following exposure to sub inhibitory concentrations of antimicrobial agents. Eur J Clin Microbiol Infect Dis 1998;17:761-6 https://doi.org/10.1007/s100960050181
  22. Kimmitt PT, Harwood CR, Barer MR. Toxin gene expression by shiga toxin-producing escherichia coli: The role of antibiotics and the bacterial SOS response. Emerg Infect Dis 2000;6:458-65 https://doi.org/10.3201/eid0605.000503
  23. Armstrong GD, Rowe PC, Goodyer P, Orrbine E, Klassen TP, Wells G, et al. A phase I study of chemically synthesized verotoxin(shiga-like toxin) pk-trisaccharide receptors attached to chromo sorb for preventing hemolytic-uremic syndrome. J Infect Dis 1995;171 :1042-5 https://doi.org/10.1093/infdis/171.4.1042
  24. Mackenzie AM, Lebel P, Orrbine E, Rowe PC, Hyde L, Chan F, et al. Sensitivities and specificities of premier E. coli O157 and premier EHEC enzyme immunoassays for diagnosis of infection with verotxin(shiga-like toxinrproducing escherichia coli. the SYNSORB pk study investigators. J Clin Microbiol 1998;36:1608-11
  25. Trachtman H, Christen E. Pathogenesis, treatment, and therapeutic trials in hemolytic uremic syndrome. Curr Opin Pediatr 1999;11:162-8 https://doi.org/10.1097/00008480-199904000-00011
  26. Takeda T, Yoshino K, Adachi E, Sato Y, Yamagata K. In vitro assessment of a chemically synthesized shiga toxin receptor analog attached to chromo sorb Ptsynsorb pk) as a specific absorbing agent of shiga toxin 1 and 2. Microbiol Immunol 1999;43:331-7 https://doi.org/10.1111/j.1348-0421.1999.tb02413.x
  27. MacConnachie AA, Todd WT. Potential therapeutic agents for the prevention and treatment of haemolytic uraemic syndrome in shiga toxin producing escherichia coli infection. Curr Opin Infect Dis 2004;17:479-82 https://doi.org/10.1097/00001432-200410000-00013
  28. Trachtman H, Cnaan A, Christen E, Gibbs K, Zhao S, Acheson DW, et al. Effect of an oral shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children: A randomized controlled trial. JAMA 200310;290: 1337-44 https://doi.org/10.1001/jama.290.10.1337
  29. Brandt J, Wong C, Mihm S, RobertsJ, Smith J, Brewer E, et al. Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics. 2002;110:371-6 https://doi.org/10.1542/peds.110.2.371
  30. Klein PJ, Bulla M, Newman RA, Muller P, Uhlenbruck G, Schaefer HE, et al. Thomsen-friedenreich antigen in haemolytic-uraemic syndrome. Lancet 197712;2:1024-5
  31. Cochran JB, Panzarino VM, Maes L Y, Tecklenburg FW. Pneumococcus-induced Tv antigen activation in hemolytic uremic syndrome and anemia. Pediatr Nephrol 2004;19:317-21 https://doi.org/10.1007/s00467-003-1382-z
  32. Stuhlinger W, Kourilsky O, Kanfer A, Sraer JD. Letter: Haemolytic-uraemic syndrome: Evidence for intravascular C3 activation. Lancet 1974 28;2:788-9
  33. Noris M, Ruggenenti P, Perna A, Orisio S, Caprioli J. Skerka C, et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: Role of factor H abnormalities. italian registry of familial and recurrent hemolytic uremic Syndrome/ Thrombotic thrombocytopenic purpura. J Am Soc Nephrol 1999;10:281-93
  34. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006 15;108:1267-79 https://doi.org/10.1182/blood-2005-10-007252
  35. Ault BH. Factor H and the pathogenesis of renal diseases. Pediatr Nephrol. 2000;14:1045-53 https://doi.org/10.1007/s004670050069
  36. Atkinson JP, Goodship TH. Complement factor H and the hemolytic uremic syndrome. J Exp Med 2007 11;204:1245-8 https://doi.org/10.1084/jem.20070664
  37. Taylor CM. Hemolytic-uremic syndrome and complement factor H deficiency: Clinical aspects. Semin Thromb Hemost 2001 27:185-90
  38. Zipfel PF. Complement factor H: Physiology and pathophysiology. Semin Thromb Hemost 2001 27:191-9
  39. Kavanagh D, Goodship TH, Richards A. Atypical haemolytic uraemic syndrome. Br Med Bull 2006;77-78:5-22
  40. Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Frerneaux-Bacchi V, et al. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 2007:44:111-22 https://doi.org/10.1016/j.molimm.2006.07.004
  41. Kavanagh D, Goodship TH. Membrane cofactor protein and factor I: Mutations and transplantation. Semin Thromb Hemost. 2006;32:155-9 https://doi.org/10.1055/s-2006-939771
  42. Geelen J. van den Dries K, Roos A, van de Kar N, de Kat Angelino C, Klasen I, et al. A missense mutation in factor I(IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol 2007;22:371-5 https://doi.org/10.1007/s00467-006-0320-2
  43. Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, et al. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol 2007:44:1835-44 https://doi.org/10.1016/j.molimm.2006.10.005
  44. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, 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; 18:2392-400 https://doi.org/10.1681/ASN.2006080811
  45. Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L. Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr 2001;138:412-7 https://doi.org/10.1067/mpd.2001.112649
  46. Gerber A, Kirchhoff-Moradpour AH, Obieglo S, Brandis M, Kirschfink M, Zipfel PF, et al. Successfu](?) therapy of hemolytic-uremic syndrome with factor H abnormality. Pediatr Nephrol 2003;18:952-5 https://doi.org/10.1007/s00467-003-1192-3
  47. Nathanson S, Frerneaux-Bacchi V, Deschenes G. Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 2001;16:554-6 https://doi.org/10.1007/s004670100609
  48. Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B, et al. Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 2005:45:415-21 https://doi.org/10.1053/j.ajkd.2004.10.018
  49. Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, et al. Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 2002 11;359:1671-2
  50. Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, et al. Hemolytic uremic syndrome: A fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation. Am J Transplant 2005;5: 1146-50 https://doi.org/10.1111/j.1600-6143.2005.00783.x
  51. Cheong HI, Lee BS, Kang HG, Hahn H, Suh KS, Ha IS, et al. Attempted treatment of factor H deficiency by liver transplantation. Pediatr Nephrol 2004;19:454-8 https://doi.org/10.1007/s00467-003-1371-2
  52. Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS, et al. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant 2006;6:1948-52 https://doi.org/10.1111/j.1600-6143.2006.01375.x
  53. Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81 https://doi.org/10.1097/01.ASN.0000060805.04118.4C
  54. te Loo DM, Levtchenko E, Furlan M, Roosendaal GP, van den Heuvel LP. Autosomal recessive inheritance of von willebrand factor-cleaving protease deficiency. Pediatr Nephrol 2000;14:762-5 https://doi.org/10.1007/PL00013432
  55. Licht C, Stapenhorst L, Simon T, Budde U, Schneppenheim R, Hoppe B. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome(TTP/HUS). Kidney Int 2004;66:955-8 https://doi.org/10.1111/j.1523-1755.2004.00841.x
  56. Tsai HM. Von willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. J Mol Med 2002;80:639-47 https://doi.org/10.1007/s00109-002-0369-8
  57. Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von willebrand factor-cleaving protease(ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J BioI Chem 2001 2;276: 41059-63 https://doi.org/10.1074/jbc.C100515200
  58. Zheng X, Nishio K, Majerus EM, Sadler JE. Cleavage of von willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. J BioI Chem. 2003 8;278:30136-41
  59. Plaimauer B, Zimmermann K, Volkel D, Antoine G, Kerschbaumer R, Jenab P, et al. Cloning, expression, and functional characterization of the von willebrand factor-cleaving protease(ADAMTS13). Blood 2002 15;100:3626-32 https://doi.org/10.1182/blood-2002-05-1397
  60. Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin Hematol 2004; 41:34-40 https://doi.org/10.1053/j.seminhematol.2003.10.002
  61. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001 4:413:488-94 https://doi.org/10.1038/35097008
  62. Veyradier A, Lavergne JM, Ribba AS, Obert B, Loirat C, Meyer D, et al. Ten candidate ADAMTS13 mutations in six french families with congenital thrombotic thrombocytopenic purpuratupshaw -schulman syndrome). J Thromb Haemost 2004;2:424-9 https://doi.org/10.1111/j.1538-7933.2004.00623.x
  63. Shibagaki Y, Matsumoto M, Kokame K, Ohba S, Miyata T, Fujimura Y, et al. Novel compound heterozygote mutations(H234Q/Rl206X) of the ADAMTS13 gene in an adult patient with upshaw-schulman syndrome showing predominant episodes of repeated acute renal failure. Nephrol Dial Transplant 2006;21:1289-92 https://doi.org/10.1093/ndt/gfk072
  64. Furlan M, Robles R, Solenthaler M, Lammle B. Acquired deficiency of von willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998 15;91:2839-46