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Genetic susceptibility to renal scar formation after urinary tract infection: a systematic review and meta-analysis of candidate gene polymorphisms

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Abstract

Identifying patients who may develop renal scarring after urinary tract infections (UTI) remains challenging, as clinical determinants explain only a portion of individual risk. An additional factor that likely affects risk is individual genetic variability. We searched for peer-reviewed articles from 1980 to December 2009 in electronic databases that reported results showing an association between gene polymorphims and renal scaring after UTI. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality using an aggregate scoring system. The 18 studies ultimately included in the review had investigated 16 polymorphisms in nine genes in association with renal scarring formation after UTI. Based on the predetermined criteria for assessing the quality of the studies, 12 studies (67%) were identified as being of poor quality design. A meta-analysis of cumulative studies showed on association between renal scarring formation after UTI and the angiotensin converting enzyme insertion/deletion polymorphism [ACE I/D; recessive model for D allele; odds ratio (OR) 1.73, 95% confidence interval (CI) 1.09–2.74, P = 0.02] or transforming growth factor (TGF)-β1 c.-509 T > C polymorphism (dominant model for T allele; OR 2.24, 95% CI 1.34–3.76, P = 0.002). However, heterogeneity among studies was large, indicating a strong difference that cannot only be explained by differences in study design. The studies reviewed in this article support a modest involvement of the vasomotor and inflammatory genes in the development of renal scarring after UTIs. This review also shows that only few possible candidate genes have been investigated for an association with renal scarring, raising the hypothesis that some gene polymorphisms may exert their effects through an interaction with as yet uninvestigated factors that may be related to geographic and/or socio-economic differences.

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References

  1. Hellström A, Hanson E, Hansson S, Hjälmås K, Jodal U (1991) Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 66:232–234

    PubMed  PubMed Central  Google Scholar 

  2. Shaikh N, Morone NE, Bost JE, Farrell MH (2008) Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 27:302–308

    PubMed  Google Scholar 

  3. Vachvanichsanong P (2007) Urinary tract infection: one lingering effect of childhood kidney diseases—review of the literature. J Nephrol 20:21–28

    PubMed  Google Scholar 

  4. Shim YH, Lee JW, Lee SJ (2009) The risk factors of recurrent urinary tract infection in infants with normal urinary systems. Pediatr Nephrol 24:309–312

    PubMed  Google Scholar 

  5. Coulthard MG (2009) Vesicoureteric reflux is not a benign condition. Pediatr Nephrol 24:227–232

    PubMed  Google Scholar 

  6. Risdon RA, Yeung CK, Ransley PG (1993) Reflux nephropathy in children submitted to unilateral nephrectomy: a clinicopathological study. Clin Nephrol 40:308–314

    CAS  PubMed  Google Scholar 

  7. Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG (1997) The characteristics of primary vesico-ureteric reflux in male and female infants with pre-natal hydronephrosis. Br J Urol 80:319–327

    CAS  PubMed  Google Scholar 

  8. Williams G, Fletcher JT, Alexander SI, Craig JC (2008) Vesicoureteral reflux. J Am Soc Nephrol 19:847–862

    CAS  PubMed  Google Scholar 

  9. Cordell HJ, Darlay R, Charoen P, Stewart A, Gullett AM, Lambert HJ, Malcolm S, Feather SA, Goodship TH, Woolf AS, Kenda RB, Goodship JA; UK VUR Study Group (2010) Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux. J Am Soc Nephrol 21:113–123

    Google Scholar 

  10. Silva JM, Diniz JS, Lima EM, Pinheiro SV, Marino VP, Cardoso LS, Colosimo EA, Silva AC, Oliveira EA (2009) Independent risk factors for renal damage in a series of primary vesicoureteral reflux: a multivariate analysis. Nephrology (Carlton) 14:198–204

    Google Scholar 

  11. Becker A, Baum M (2006) Obstructive uropathy. Early Hum Dev 82:15–22

    PubMed  Google Scholar 

  12. Webb NJ, Brenchley PE (2004) Cytokines and cell adhesion molecules in the inflammatory response during acute pyelonephritis. Nephron Exp Nephrol 96:e1–e6

    CAS  PubMed  Google Scholar 

  13. Lane MC, Mobley HL (2007) Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney. Kidney Int 72:19–25

    CAS  PubMed  Google Scholar 

  14. Godaly G, Bergsten G, Hang L, Fischer H, Frendéus B, Lundstedt AC, Samuelsson M, Samuelsson P, Svanborg C (2001) Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection. J Leukoc Biol 69:899–906

    CAS  PubMed  Google Scholar 

  15. Coulthard MG, Vernon SJ, Lambert HJ, Matthews JNS (2003) A nurse led education and direct access service for the management of urinary tract infections in children: prospective controlled trial. Br Med J 327:656–659

    Google Scholar 

  16. Riccabona M, Fotter R (2004) Urinary tract infection in infants and children: an update with special regard to the changing role of reflux. Eur Radiol 14:L78–L88

    PubMed  Google Scholar 

  17. Lu JC, Coca SG, Patel UD, Cantley L, Parikh CR; Translational Research Investigating Biomarkers and Endpoints for Acute Kidney Injury (TRIBE-AKI) Consortium (2009) Searching for genes that matter in acute kidney injury: a systematic review. Clin J Am Soc Nephrol 4:1020–1031

    Google Scholar 

  18. Smellie JM, Shaw PJ, Prescod NP, Bantock HM (1988) 99mTc dimercaptosuccinic acid (DMSA) scan in patients with established radiological renal scarring. Arch Dis Child 63:1315–1319

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Little J (2006) HuGE review handbook, version 1.0. HuGENet Canada Coordinating Centre, Ottawa, Ontario, Canada. Available at: https://doi.org/www.hugenet.ca/. Accessed Feb 2008

  20. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett N (2009) STrengthening the REporting of Genetic Association studies (STREGA): an extension of the STROBE Statement. Ann Intern Med 150:206–215

    PubMed  Google Scholar 

  21. Cochrane Collaboration (2008) Review Manager (RevMan) computer program, version 5.0. The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen

  22. Ioannidis JP, Boffetta P, Little J, O'Brien TR, Uitterlinden AG, Vineis P, Balding DJ, Chokkalingam A, Dolan SM, Flanders WD, Higgins JP, McCarthy MI, McDermott DH, Page GP, Rebbeck TR, Seminara D, Khoury MJ (2008) Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 37:120–132

    PubMed  Google Scholar 

  23. Minelli C, Granell R, Newson R, Rose-Zerilli MJ, Torrent M, Ring SM, Holloway JW, Shaheen SO, Henderson JA (2010) Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data. Int J Epidemiol 39:539–562

    PubMed  Google Scholar 

  24. Karoly E, Fekete A, Banki NF, Szebeni B, Vannay A, Szabo AJ, Tulassay T, Reusz GS (2007) Heat shock protein 72 (HSPA1B) gene polymorphism and Toll-like receptor (TLR) 4 mutation are associated with increased risk of urinary tract infection in children. Pediatr Res 61:371–374

    CAS  PubMed  Google Scholar 

  25. Frendéus B, Godaly G, Hang L, Karpman D, Svanborg C (2001) Interleukin-8 receptor deficiency confers susceptibility to acute pyelonephritis. J Infect Dis 183:S56–S60

    PubMed  Google Scholar 

  26. Hang L, Frendeus B, Godaly G, Svanborg C (2000) Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J Infect Dis 182:1738–1748

    CAS  PubMed  Google Scholar 

  27. Lundstedt AC, Leijonhufvud I, Ragnarsdottir B, Karpman D, Andersson B, Svanborg C (2007) Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection. J Infect Dis 195:1227–1234

    PubMed  Google Scholar 

  28. Smithson A, Sarrias MR, Barcelo J, Suarez B, Horcajada JP, Soto SM, Soriano A, Vila J, Martinez JA, Vives J, Mensa J, Lozano F (2005) Expression of interleukin-8 receptors (CXCR1 and CXCR2) in premenopausal women with recurrent urinary tract infections. Clin Diagn Lab Immunol 12:1358–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hawn TR, Scholes D, Li SS, Wang H, Yang Y, Roberts PL, Stapleton AE, Janer M, Aderem A, Stamm WE, Zhao LP, Hooton TM (2009) Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One 4:e5990

    PubMed  PubMed Central  Google Scholar 

  30. Tabel Y, Berdeli A, Mir S (2007) Association of TLR2 gene Arg753Gln polymorphism with urinary tract infection in children. Int J Immunogenet 34:399–405

    CAS  PubMed  Google Scholar 

  31. Ragnarsdóttir B, Samuelsson M, Gustafsson MC, Leijonhufvud I, Karpman D, Svanborg C (2007) Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J Infect Dis 196:475–484

    PubMed  Google Scholar 

  32. Yim HE, Bae IS, Yoo KH, Hong YS, Lee JW (2007) Genetic control of VEGF and TGF-beta1 gene polymorphisms in childhood urinary tract infection and vesicoureteral reflux. Pediatr Res 62:183–187

    CAS  PubMed  Google Scholar 

  33. Artifoni L, Negrisolo S, Montini G, Zucchetta P, Molinari PP, Cassar W, Destro R, Anglani F, Rigamonti W, Zacchello G, Murer L (2007) Interleukin-8 and CXCR1 receptor functional polymorphisms and susceptibility to acute pyelonephritis. J Urol 177:1102–1106

    CAS  PubMed  Google Scholar 

  34. Cotton SA, Gbadegesin RA, Williams S, Brenchley PE, Webb NJ (2002) Role of TGF-beta1 in renal parenchymal scarring following childhood urinary tract infection. Kidney Int 61:61–67

    CAS  PubMed  Google Scholar 

  35. Gbadegesin RA, Cotton SA, Watson CJ, Brenchley PE, Webb NJ (2006) Association between ICAM-1 Gly-Arg polymorphism and renal parenchymal scarring following childhood urinary tract infection. Int J Immunogenet 33:49–53

    CAS  PubMed  Google Scholar 

  36. Brodkiewicz A, Adler G, Woźniak S, Szychot E, Peregud-Pogorzelski J, Fydryk J, Ciechanowicz A (2004) Polymorphism of genes of the renin-angiotensin (RA) system and TGF-β1 promoter in pathogenesis of reflux nephropathy in children - preliminary report. Przegl Pediatryczny 34:205–210

    Google Scholar 

  37. Dudley J, Johnston A, Gardner A, McGraw M (2002) The deletion polymorphism of the ACE gene is not an independent risk factor for renal scarring in children with vesico-ureteric reflux. Nephrol Dial Transplant 17:652–654

    CAS  PubMed  Google Scholar 

  38. Cho SJ et al (2002) ACE gene polymorphism and renal scar in children with acute pyelonephritis. Pediatr Nephrol 17:491–495

    PubMed  Google Scholar 

  39. Ece A, Tekes S, Gürkan F, Bilici M, Budak T (2005) Polymorphisms of the angiotensin converting enzyme and angiotensin II type 1 receptor genes and renal scarring in non uropathic children with recurrent urinary tract infection. Nephrology 10:377–381

    CAS  PubMed  Google Scholar 

  40. Erdoğan H, Mir S, Serdaroğlu E, Berdeli A, Aksu N (2005) Is ACE gene polymorphism a risk factor for renal scarring with low-grade reflux? Pediatr Nephrol 19:734–737

    Google Scholar 

  41. Haszon I, Friedman AL, Papp F, Bereczki C, Baji S, Bodrogi T, Károly E, Endreffy E, Túri S (2002) ACE gene polymorphism and renal scarring in primary vesicoureteric reflux. Pediatr Nephrol 17:1027–1031

    PubMed  Google Scholar 

  42. Hussein A, Askar E, Elsaeid M, Schaefer F (2010) Functional polymorphisms in transforming growth factor-beta-1 (TGF{beta}-1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection. Nephrol Dial Transplant 25:779–785

    CAS  PubMed  Google Scholar 

  43. Kowalewska-Pietrzak M, Klich I, Mlynarski W (2008) TGF-beta1 gene polymorphisms and primary vesicoureteral reflux in childhood. Pediatr Nephrol 23:2195–2200

    PubMed  Google Scholar 

  44. Kuroda S, Puri P (2007) Lack of association of IL8 gene polymorphisms with familial vesico-ureteral reflux. Pediatr Surg Int 23:441–445

    PubMed  Google Scholar 

  45. Ohtomo Y, Nagaoka R, Kaneko K, Fukuda Y, Miyano T, Yamashiro Y (2001) Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux. Pediatr Nephrol 16:648–652

    CAS  PubMed  Google Scholar 

  46. Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, Kocak H, Erbas B, Unsal I, Tuncbilek E (1999) Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis 34:140–145

    CAS  PubMed  Google Scholar 

  47. Pardo R, Málaga S, Coto E, Navarro M, Alvarez V, Espinosa L, Alvarez R, Vallo A, Loris C, Braga S (2003) Renin-angiotensin system polymorphisms and renal scarring. Pediatr Nephrol 18:110–114

    PubMed  Google Scholar 

  48. Pardo R, Málaga S, Alvarez V, Coto E (2007) Vesicoureteric reflux and tumor necrosis factor-alpha gene polymorphism. J Pediatr Urol 3:24–27

    PubMed  Google Scholar 

  49. Park HW, Koo JW, Kim JS, Ha IS, Cheong HI, Choi Y (2000) Association of angiotensin I converting enzyme gene polymorphism with reflux nephropathy in children. Nephron 86:52–55

    CAS  PubMed  Google Scholar 

  50. Savvidou A, Bitsori M, Choumerianou DM, Karatzi M, Kalmanti M, Galanakis E (2010) Polymorphisms of the TNF-alpha and ACE genes, and renal scarring in infants with urinary tract infection. J Urol 183:684–687

    CAS  PubMed  Google Scholar 

  51. Sekerli E, Katsanidis D, Vavatsi N, Makedou A, Gatzola M (2009) ACE gene insertion/deletion polymorphism and renal scarring in children with urinary tract infections. Pediatr Nephrol 24:1975–1980

    PubMed  Google Scholar 

  52. Solari V, Ennis S, Cascio S, Puri P (2004) Tumor necrosis factor-alpha gene polymorphism in reflux nephropathy. J Urol 172:1604–1606

    CAS  PubMed  Google Scholar 

  53. Solari V, Owen D, Puri P (2005) Association of transforming growth factor-beta1 gene polymorphism with reflux nephropathy. J Urol 174:1609–1611

    CAS  PubMed  Google Scholar 

  54. Yoneda A, Cascio S, Oue T, Chertin B, Puri P (2002) Risk factors for the development of renal parenchymal damage in familial vesicoureteral reflux. J Urol 168:1704–1707

    CAS  PubMed  Google Scholar 

  55. Merguerian PA, Sverrisson EF, Herz DB, McQuiston LT (2010) Urinary tract infections in children: recommendations for antibiotic prophylaxis and evaluation. An evidence-based approach. Curr Urol Rep 11:98–108

    PubMed  Google Scholar 

  56. Jahnukainen T, Chen M, Celsi G (2005) Mechanisms of renal damage owing to infection. Pediatr Nephrol 20:1043–1053

    PubMed  Google Scholar 

  57. Fogo AB (2007) Mechanisms of progression of chronic kidney disease. Pediatr Nephrol 22:2011–2022

    PubMed  PubMed Central  Google Scholar 

  58. Faust WC, Diaz M, Pohl HG (2009) Incidence of post-pyelonephritic renal scarring: a meta-analysis of the dimercapto-succinic acid literature. J Urol 181:290–297

    PubMed  Google Scholar 

  59. Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, Hodson EM, Carapetis JR, Cranswick NE, Smith G, Irwig LM, Caldwell PH, Hamilton S, Roy LP, Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators (2009) Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 361:1748–1759

    CAS  PubMed  Google Scholar 

  60. Daly AK (2010) Pharmacogenetics and human genetic polymorphisms. Biochem J 429:435–449

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Life and Reproduction Sciences, Section of Pediatrics, University of Verona, Verona, Italy

    Marco Zaffanello

  2. Department of Medicine and Public Health, Section of Hygiene and Preventive, Environmental and Occupational Medicine, University of Verona, Verona, Italy

    Stefano Tardivo

  3. Division of Neonatology, Catholic University of Sacred Heart, Rome, Italy

    Luigi Cataldi

  4. Neonatal Intensive Care Unit, University of Cagliari, Cagliari, Italy

    Vassilios Fanos

  5. Neonatal and Paediatric Intensive Care Unit, Division of Paediatrics, Major City Hospital, Verona, Italy

    Paolo Biban

  6. Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy

    Giovanni Malerba

  7. Department of Life and Reproduction Sciences, University of Verona, Piazzale L. Scuro, 10, 37134, Verona, Italy

    Marco Zaffanello

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  1. Marco Zaffanello
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Zaffanello, M., Tardivo, S., Cataldi, L. et al. Genetic susceptibility to renal scar formation after urinary tract infection: a systematic review and meta-analysis of candidate gene polymorphisms. Pediatr Nephrol 26, 1017–1029 (2011). https://doi.org/10.1007/s00467-010-1695-7

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