Seminars in Nephrology
Volume 28, Issue 5 , Pages 499-509 , September 2008

Multiple Organ Dysfunction Syndrome in Children With Sepsis: Role of Genetic Factors

  • Orfeas Liangos, MD
    • ,
  • Bertrand L. Jaber, MD, MS

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Bertrand L. Jaber, MD, Department of Medicine, Division of Nephrology, Caritas St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135

References 

  1. Castellanos-Ortega A, Delgado-Rodriguez M, Llorca J, Sanchez Buron P, Mencia Bartolome S, Soult Rubio A, et al. A new prognostic scoring system for meningococcal septic shock in children. Comparison with three other scoring systems. Intensive Care Med. 2002;28:341–351
  2. Bagshaw SM, Bellomo R. Fluid resuscitation and the septic kidney. Curr Opin Crit Care. 2006;12:527–530
  3. Licari E, Calzavacca P, Ronco C, Bellomo R. Fluid resuscitation and the septic kidney: the evidence. Contrib Nephrol. 2007;156:167–177
  4. Nussbaum R, McInnes R, Willard H. Genetic variation in individuals: mutation and polymorphism. In: Thompson & Thompson genetics in medicine. Philadelphia: WB Saunders Company; 2001;p. 79–94
  5. van Deventer S. Cytokine and cytokine receptor polymorphisms in infectious disease. Intensive Care Med. 2000;26(Suppl 1):S98–S1002
  6. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–874
  7. Jaber BL, Pereira BJG. Inflammatory mediators in sepsis: rationale for extracorporeal therapies. Am J Kidney Dis. 1996;28:S35–S49
  8. Pinsky MRVJ, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest. 1993;103:565–575
  9. Casey LCBR, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med. 1993;119:771–778
  10. Scumpia PO, Moldawer LL. Biology of interleukin-10 and its regulatory roles in sepsis syndromes. Crit Care Med. 2005;33:S468–S471
  11. Song M, Kellum JA. Interleukin-6. Crit Care Med. 2005;33:S463–S465
  12. Dinarello CA. Interleukin-1beta. Crit Care Med. 2005;33:S460–S462
  13. Koch T. Origin and mediators involved in sepsis and the systemic inflammatory response syndrome. Kidney Int. 1998;53(Suppl 64):S66–S69
  14. Opal S, DePalo V. Anti-inflammatory cytokines. Chest. 2000;117:1162–1172
  15. Tabardel Y, Duchateau J, Schmartz D, Marecaux G, Shahla M, Barvais L, et al. Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men. Surgery. 1996;119:76–80
  16. Fillinger MP, Rassias AJ, Guyre PM, Sanders JH, Beach M, Pahl J, et al. Glucocorticoid effects on the inflammatory and clinical responses to cardiac surgery. J Cardiothorac Vasc Anesth. 2002;16:163–169
  17. Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW. An allelic polymorphism within the human tumor necrosis factor-alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med. 1993;177:557–560
  18. Morse H, Olomolaiye O, Wood N, Keen L, Bidwell J. Induced heteroduplex genotyping of TNF-alpha, IL-1beta, IL-6 and IL-10 polymorphisms associated with transcriptional regulation. Cytokine. 1999;11:789–795
  19. Abraham LJ, Kroeger KM. Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol. 1999;66:562–566
  20. Wilson AGSJ, McDowell TL, McDewitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997;94:3195–3199
  21. Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-α promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–399
  22. Warzocha K, Ribeiro P, Bienvenu J. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome. Blood. 1998;91:3574–3581
  23. Louis E, Franchimont D, Piron A. Tumor necrosis factor gene polymorphism influences TNF-alpha production in lipopolysaccharide-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998;113:401–406
  24. Mira J-P, Cariou A, Grall F, Delclaux C, Losser M-R, Heshmati F, et al. Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282:561–568
  25. Tang GJ, Huang SL, Yien HW, Chen WS, Chi CW, Wu CW, et al. Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med. 2000;28:2733–2736
  26. Weitkamp JH, Stuber F, Bartmann P. Pilot study assessing TNF gene polymorphism as a prognostic marker for disease progression in neonates with sepsis. Infection. 2000;28:92–96
  27. Wunderink RG, Waterer GW, Cantor RM, Quasney MW. Tumor necrosis factor gene polymorphisms and the variable presentation and outcome of community-acquired pneumonia. Chest. 2002;121:87S
  28. Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor-α promoter region may be associated with death from meningococcal disease. J Infect Dis. 1996;174:878–880
  29. Mcguire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation of the TNF-α promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–510
  30. Cabrera M, Shaw MA, Sharples C. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med. 1995;182:1259–1264
  31. Jaber B, Rao M, Guo D, Balakrishnan V, Perianayagam M, Freeman R, et al. Cytokine promoter gene polymorphisms and mortality in acute renal failure. Cytokine. 2004;25:212–219
  32. Treszl A, Toth-Heyn P, Kocsis I, Nobilis A, Schuler A, Tulassay T, et al. Interleukin genetic variants and the risk of renal failure in infants with infection. Pediatr Nephrol. 2002;17:713–717
  33. Bokodi G, Treszl A, Derzbach L, Balogh A, Vasarhelyi B. The association of the carrier state of the tumor necrosis factor-alpha (TNFalpha) -308A allele with the duration of oxygen supplementation in preterm neonates. Eur Cytokine Netw. 2005;16:78–80
  34. Abraham L, Du D, Zahedi K, Dawkins R, Whitehead A. Haplotypic polymorphisms of the TNFB gene. Immunogenetics. 1991;33:50–53
  35. Pociot F, Molvig J, Wogensen L, Worsaae H, Dalboge H, Baek L, et al. A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus. Scand J Immunol. 1991;33:37–49
  36. Stuber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996;24:381–384
  37. Majetschak M, Flohe S, Obertacke U, Schroder J, Staubach K, Nast-Kolb D, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg. 1999;230:207–214
  38. Heesen M, Kunz D, Bachmann-Mennenga B, Merk H, Bloemeke B. Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: association with TNF-alpha response of granulocytes to endotoxin stimulation. Crit Care Med. 2003;31:211–214
  39. Read R, Cannings C, Naylor S, Timms J, Maheswaran R, Borrow R, et al. Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease. Ann Intern Med. 2003;138:534–541
  40. Virta M, Hurme M, Helminen M. Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures. Pediatr Neurol. 2002;26:192–195
  41. Berger P, McConnell J, Nunn M, Kornman K, Sorrell J, Stephenson K, et al. C-reactive protein levels are influenced by common IL-1 gene variations. Cytokine. 2002;17:171–174
  42. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1β production in vitro. Scand J Immunol. 1998;47:195–198
  43. Andus T, Daig R, Vogl D, Aschenbrenner E, Lock G, Hollerbach S, et al. Imbalance of the interleukin 1 system in colonic mucosa—association with intestinal inflammation and interleukin 1 receptor antagonist [corrected] genotype 2. Gut. 1997;41:651–657
  44. Tountas N, Casini-Raggi V, Yang H, Di Giovine F, Vecchi M, Kam L, et al. Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis. Gastroenterology. 1999;117:806–813
  45. Fang X, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med. 1999;27:1330–1334
  46. Ma P, Chen D, Pan J, Du B. Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med. 2002;30:1046–1050
  47. Barton B. IL-6: insights into novel biological activities. Clin Immunol Immunopathol. 1997;85:16–20
  48. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–1376
  49. Fernandez-Real JM, Broch M, Vendrell J, Richart C, Ricart W. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab. 2000;85:1331–1333
  50. Schluter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S, et al. Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis. Crit Care Med. 2002;30:32–37
  51. Baier RJ, Loggins J, Yanamandra K. IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants. BMC Med. 2006;4:10
  52. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 1999;42:1101–1108
  53. van der Pol WLHT, Vidarsson G, van der Linden MW, Jansen MD, Keijsers V, de Straat FG, et al. Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease. J Infect Dis. 2001;184:1548–1555
  54. Gallagher P, Lowe G, Fitzgerald T, Bella A, Greene C, McElvaney N, et al. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax. 2003;58:154–156
  55. Jaber B, Liangos O, Pereira B, Balakrishnan V. Polymorphism of immuno-modulatory cytokine genes: implications in acute renal failure. Blood Purif. 2004;22:101–111
  56. Yanamandra K, Boggs P, Loggins J, Baier RJ. Interleukin-10 -1082 G/A polymorphism and risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants. Pediatr Pulmonol. 2005;39:426–432
  57. Hoebee B, Bont L, Rietveld E, van Oosten M, Hodemaekers HM, Nagelkerke NJ, et al. Influence of promoter variants of interleukin-10, interleukin-9, and tumor necrosis factor-alpha genes on respiratory syncytial virus bronchiolitis. J Infect Dis. 2004;189:239–247
  58. Segerer S, Alpers CE. Chemokines and chemokine receptors in renal pathology. Curr Opin Nephrol Hypertens. 2003;12:243–249
  59. Segerer S, Nelson PJ. Chemokines in renal diseases. Sci World J. 2005;5:835–844
  60. Miura M, Fu X, Zhang QW, Remick DG, Fairchild RL. Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. Am J Pathol. 2001;159:2137–2145
  61. Maier S, Emmanuilidis K, Entleutner M, Zantl N, Werner M, Pfeffer K, et al. Massive chemokine transcription in acute renal failure due to polymicrobial sepsis. Shock. 2000;14:187–192
  62. Jiang Z, Okhuysen P, Guo D, He R, King T, DuPont H, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea polymorphism in the IL-8 promotor region at position -251. J Infect Dis. 2003;188:506–511
  63. Hull J, Thomson A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax. 2000;55:1023–1027
  64. Kruger B, Schroppel B, Ashkan R, Marder B, Zulke C, Murphy B, et al. A monocyte chemoattractant protein-1 (MCP-1) polymorphism and outcome after renal transplantation. J Am Soc Nephrol. 2002;13:2585–2589
  65. Amoli MM, Thomson W, Hajeer AH, Calvino MC, Garcia-Porrua C, Ollier WE, et al. Interleukin 8 gene polymorphism is associated with increased risk of nephritis in cutaneous vasculitis. J Rheumatol. 2002;29:2367–2370
  66. Amanatidou V, Sourvinos G, Apostolakis S, Neonaki P, Tsilimigaki A, Krambovitis E, et al. RANTES promoter gene polymorphisms and susceptibility to severe respiratory syncytial virus-induced bronchiolitis. Pediatr Infect Dis J. 2008;27:38–42
  67. Macdonald J, Galley H, Webster N. Oxidative stress and gene expression in sepsis. Br J Anaesth. 2003;90:221–232
  68. Hoy A, Leininger-Muller B, Kutter D, Siest G, Visvikis S. Growing significance of myeloperoxidase in non-infectious diseases. Clin Chem Lab Med. 2002;40:2–8
  69. Ursini F, Maiorino M, Brigelius-Flohe R, Aumann K, Roveri A, Schomburg D, et al. Diversity of glutathione peroxidases. Methods Enzymol. 1995;252:38–53
  70. Flohe L. Glutathione peroxidase. Basic Life Sci. 1988;49:663–668
  71. Sies H. Glutathione and its role in cellular functions. Free Radic Biol Med. 1999;27:916–921
  72. Forsberg L, de Faire U, Morgenstern R. Oxidative stress, human genetic variation, and disease. Arch Biochem Biophys. 2001;389:84–93
  73. Fukai T, Folz R, Landmesser U, Harrison D. Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc Res. 2002;55:239–249
  74. Baliga R, Ueda N, Walker P, Shah S. Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev. 1999;31:971–997
  75. Druml W, Schwarzenhofer M, Apsner R, Horl W. Fat-soluble vitamins in patients with acute renal failure. Miner Electrolyte Metab. 1998;24:220–226
  76. Metnitz P, Fischer M, Bartens C, Steltzer H, Lang T, Druml W. Impact of acute renal failure on antioxidant status in multiple organ failure. Acta Anaesthesiol Scand. 2000;44:236–240
  77. Balakrishnan V, Blumberg J, Pereira B, Jaber B. Antioxidant and oxidative stress indices in dialysis-dependent acute renal failure. Blood Purif. 2003;21:213–219
  78. Inoue N, Kawashima S, Kanazawa K, Yamada S, Akita H, Yokoyama M. Polymorphism of the NADH/NADPH oxidase p22phox gene in patients with coronary artery disease. Circulation. 1998;97:135–137
  79. Guzik T, West N, Black E, McDonald D, Ratnatunga C, Pillai R, et al. Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. Circulation. 2000;102:1744–1747
  80. Hodgkinson AD, Millward BA, Demaine AG. Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes. Diabetes Care. 2003;26:3111–3115
  81. Forsberg L, Lyrenas L, de Faire U, Morgenstern R. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Radic Biol Med. 2001;30:500–505
  82. Nadif R, Mintz M, Jedlicka A, Bertrand JP, Kleeberger SR, Kauffmann F. Association of CAT polymorphisms with catalase activity and exposure to environmental oxidative stimuli. Free Radic Res. 2005;39:1345–1350
  83. Perianayagam M, Liangos O, Kolyada A, Wald R, MacKinnon R, Li L, et al. NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007;18:255–263
  84. Platonov AE, Shipulin GA, Vershinina IV, Dankert J, van de Winkel JG, Kuijper EJ. Association of human Fc gamma RIIa (CD32) polymorphism with susceptibility to and severity of meningococcal disease. Clin Infect Dis. 1998;27:746–750
  85. Domingo P, Muniz-Diaz E, Baraldes MA, Arilla M, Barquet N, Pericas R, et al. Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease. Am J Med. 2002;112:19–25
  86. Domingo P, Muniz-Diaz E, Baraldes MA, Arilla M, Barquet N, Pericas R, et al. Relevance of genetically determined host factors to the prognosis of meningococcal disease. Eur J Clin Microbiol Infect Dis. 2004;23:634–637
  87. Smith I, Vedeler C, Halstensen A. FcgammaRIIa and FcgammaRIIIb polymorphisms were not associated with meningococcal disease in Western Norway. Epidemiol Infect. 2003;130:193–199
  88. Bathum L, Hansen H, Teisner B, Koch C, Garred P, Rasmussen K, et al. Association between combined properdin and mannose-binding lectin deficiency and infection with Neisseria meningitidis. Mol Immunol. 2006;43:473–479
  89. Haralambous E, Dolly SO, Hibberd ML, Litt DJ, Udalova IA, O'Dwyer C, et al. Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients. Scand J Infect Dis. 2006;38:764–771
  90. Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA, de Groot R, et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet. 1999;354:556–560
  91. Westendorp RG, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet. 1999;354:561–563
  92. Geishofer G, Binder A, Muller M, Zohrer B, Resch B, Muller W, et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur J Pediatr. 2005;164:486–490
  93. Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M. Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children. Crit Care Med. 2003;31:2788–2793
  94. Binder A, Endler G, Muller M, Mannhalter C, Zenz W. 4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia. J Thromb Haemost. 2007;5:2049–2054
  95. Kremer Hovinga JA, Franco RF, Zago MA, Ten Cate H, Westendorp RG, Reitsma PH. A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease. J Thromb Haemost. 2004;2:54–57
  96. Read R, Camp N, di Giovine F, Borrow R, Kaczmarski E, Chaudhary A, et al. An interleukin-1 genotype is associated with fatal outcome of meningococcal disease. J Infect Dis. 2000;182:1557–1560
  97. Endler G, Marculescu R, Starkl P, Binder A, Geishofer G, Muller M, et al. Polymorphisms in the interleukin-1 gene cluster in children and young adults with systemic meningococcemia. Clin Chem. 2006;52:511–514
  98. Harding D, Baines PB, Brull D, Vassiliou V, Ellis I, Hart A, et al. Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism. Am J Respir Crit Care Med. 2002;165:1103–1106
  99. Balding J, Healy CM, Livingstone WJ, White B, Mynett-Johnson L, Cafferkey M, et al. Genomic polymorphic profiles in an Irish population with meningococcaemia: is it possible to predict severity and outcome of disease?. Genes Immun. 2003;4:533–540
  100. Ridker P, Stampfer M. Assessment of genetic markers for coronary thrombosis: promise and precaution. Lancet. 1999;353:687–688
  101. Newman TB, Browner WS, Hulley SB. Enhancing causal inference in observational studies. In:  Hulley SB,  Cummings SR editor. Designing clinical research. Baltimore: Williams & Wilkins; 1988;p. 98–109
  102. Nabel E. Genomic medicine: cardiovascular disease. N Engl J Med. 2003;349:60–72
  103. Ioannidis JP, Trikalinos TA. Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials. J Clin Epidemiol. 2005;58:543–549
  104. Rosenthal N, Schwartz R. In search of perverse polymorphisms. N Engl J Med. 1998;338:122–124
  105. Star RA. Treatment of acute renal failure. Kidney Int. 1998;54:1817–1831
  106. Molitoris BA. Transitioning to therapy in ischemic acute renal failure. J Am Soc Nephrol. 2003;14:265–267
  107. Jaber BL, Liangos O, Pereira BJ, Balakrishnan VS. Polymorphism of immunomodulatory cytokine genes: implications in acute renal failure. Blood Purif. 2004;22:101–111
  108. Aidoo M, McElroy PD, Kolczak MS, Terlouw DJ, ter Kuile FO, Nahlen B, et al. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX. Genet Epidemiol. 2001;21:201–211

 This work was supported by a grant from the National Institutes of Health (DK065102 to B.L.J.), and by a grant from the American Heart Association (0535367N to O.L.).

PII: S0270-9295(08)00119-8

doi: 10.1016/j.semnephrol.2008.05.011

Seminars in Nephrology
Volume 28, Issue 5 , Pages 499-509 , September 2008

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