Urine heat shock protein 70 levels as a marker of urinary tract infection in children

Abstract

Background

Heat shock proteins (HSPs) are a multi-family group of proteins which are upregulated by the cell in response to exposure to hazardous (stress) factors, including infectious agents, to prevent changes in protein structure. The aim of our study was to assess whether urine levels of the 70-kDa family of HSPs (HSP70s) increase in children with urinary tract infection (UTI) and to determine the optimal urine (u) HSP70 cut-off level to predict UTI in children.

Methods

Forty patients with symptomatic UTI (UTI group), 30 healthy children (control group), 21 asymptomatic patients with proven bacterial contamination in their urine culture (contamination group) and 30 patients with fever caused by other infections (non-UTI infection group) were enrolled in the study. Random urine samples were obtained for measurement of HSP70 and creatinine (Cr) from all groups. Urine was collected prior to the treatment of UTI at the time of presentation and after treatment. Urine HSP70 levels were measured by enzyme-linked immunosorbent analysis. A dimercaptosuccinic acid (DMSA) scan was performed at 5–7 days after presentation in UTI group to distinguish patients with acute pyelonephritis from those with cystitis; based on this scan, no patients had acute pyelonephritis. Patients were classified with pyelonephritis in the presence of all of the following signs: axillary fever of ≥39 °C, leukocytosis and positivity for C-reactive protein.

Results

The mean urine HSP70:Cr ratio (uHSP70/Cr) prior to treatment was significantly higher in the UTI group (449.86 ± 194.33 pg/mg) than in the control, contamination and non-UTI infection groups (39.93 ± 47.61, 32.43 ± 9.09 and 45.14 ± 19.76, respectively; p = 0.0001). Using a cut-off of 158 pg/mg uHSP70/Cr for the prediction of UTI, the sensitivity and specificity of the assay were 100 and 100 %, respectively (area under the time–concentration curve = 1). The uHSP70/Cr was highest in the patients with clinical pyelonephritis (p = 0.001). Mean uHSP70/Cr after treatment decreased to 60.68 ± 51.11 pg/mg in UTI group (p = 0 .0001).

Conclusions

Our findings suggest that elevated uHSP70/Cr may be a useful biomarker for the prediction of UTI in children, with a high sensitivity and specificity, and that they may help to distinguish UTI from other infections as well as bacterial contamination of the urine.

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References

  1. 1.

    Bensman A, Dunand O, Ulinski T (2009) Pediatric nephrology, 6th edition. Springer, Berlin Heidelberg New York

  2. 2.

    Roberts KB (2011) Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 128:595–610

    Article  PubMed  Google Scholar 

  3. 3.

    Williams G, Craig C (2008) Comprehensive pediatric nephrology, 1st edn. Mosby Elsevier, Philadelphia, pp 539–548

    Google Scholar 

  4. 4.

    National Institute for Health and Clinical Excellence (NICE) Guideline (2007). Urinary tract infection in children: diagnosis, treatment and long-term management. Urinary tract infection in children. RCOG Press, London. Available at: http://guidance.nice.org.k/CG054

  5. 5.

    Beck FX, Neuhofer W, Müller E (2000) Molecular chaperones in the kidney: distribution, putative roles and regulation. Am J Phhysiol Renal Physiol 279:203–215

    Google Scholar 

  6. 6.

    Garrido C, Gurbuxani S, Ravagnan L, Kroemer G (2001) Heat shock proteins: endogenous modulators of apoptotic cell death. Biochem Biophys Res Commun 286:433–442

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Hertting O, Khalil A, Jaremko G, Chromek M, Li YH, Bakhiet M, Bartfai T, Tullus K, Brauner A (2003) Enhanced chemokine response in experimental acute Escherichia coli pyelonephritis in IL-1beta-deficient mice. Clin Exp Immunol 131:225–233

  8. 8.

    Ben Mkaddem S, Chassin C, Vandewalle A (2010) Contribution of renal tubule epithelial cells in the innate immune response during renal bacterial infections and ischemia-reperfusion injury. Chang Gung Med J 33:225–240

    PubMed  Google Scholar 

  9. 9.

    Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Davies EL, Bacelar MM, Marshall MJ, Johnson E, Wardle TD, Andrew SM, Williams JH (2006) Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL. Clin Exp Immunol 145:183–189

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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  Article  PubMed  Google Scholar 

  12. 12.

    Committee on Quality Improvement, Subcommittee on Urinary Tract Infection (1999) Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 103:843–852; Erratum 103:1052, 104:118, and 105:141

  13. 13.

    Piepsz A, Colarinha P, Gordon I, Hahn K, Kabasakal L, Mann M, Mitjavila M, Olivier P, Piepsz A, Porn U, Roca I, Sixt R, van Velzen J, Paediatric Committee of the European Association of Nuclear Medicine (2001) Guidelines for 99mTc-DMSA scintigraphy in children. Eur J Nucl Med 28:37–41

    Google Scholar 

  14. 14.

    Schwartz GJ, Feld LG, Langford DJ (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58(2):259–263

    CAS  PubMed  Google Scholar 

  15. 15.

    Pesce MA (2007) Reference ranges for laboratory tests and procedures. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (eds) Nelson textbook of pediatrics, 18th edn. Saunders, Philadelphia, pp 2943–2954

    Google Scholar 

  16. 16.

    Manucha W (2014) HSP70 family in the renal inflammatory response. Inflamm Allergy Drug Targets 13:235–240

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Tang D, Kang R, Cao L, Zhang G, Yu Y, Xiao W, Wang H, Xiao X (2008) A pilot study to detect high mobility group box 1 and heat shock protein 72 in cerebrospinal fluid of pediatric patients with meningitis. Crit Care Med 36:291–295

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Varano Della Vergiliana JF, Lansley SM, Porcel JM, Bielsa S, Brown JS, Creaney J, Temple SE, Waterer GW, Lee YC (2013) Bacterial infection elicits heat shock protein 72 release from pleural mesothelial cells. PLoS One 8, e63873

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Williams GJ, Macaskill P, Chan SF, Turner RM, Hodson E, Craig JC (2010) Absolute and relative accuracy of rapid urine tests for urinary tract infection in children: a meta-analysis. Lancet Infect Dis 10(4):240–250

    Article  PubMed  Google Scholar 

  20. 20.

    Margel D, Pevsner-Fischer M, Baniel J, Yossepowitch O, Cohen IR (2011) Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer. Eur Urol 59:113–119

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Molinas SM, Rosso M, Wayllace NZ, Pagotto MA, Pisani GB, Monasterolo LA, Trumper L (2010) Heat shock protein 70 induction and its urinary excretion in a model of acetaminophen nephrotoxicity. Pediatr Nephrol 25:1245–1253

    Article  PubMed  Google Scholar 

  22. 22.

    Mueller T, Bidmon B, Pichler P, Arbeiter K, Ruffingshofer D, VanWhy SK, Aufricht C (2003) Urinary heat shock protein-72 excretion in clinical and experimental renal ischemia. Pediatr Nephrol 18:97–99

    PubMed  Google Scholar 

  23. 23.

    Lebherz-Eichinger D, Ankersmit HJ, Hacker S, Hetz H, Kimberger O, Schmidt EM, Reiter T, Hörl WH, Haas M, Krenn CG, Roth GA (2012) HSP27 and HSP70 serum and urine levels in patients suffering from chronic kidney disease. Clin Chim Acta 413:282–286

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Lebherz-Eichinger D, Krenn CG, Roth GA (2013) Keratin 18 and heat-shock protein in chronic kidney disease. Adv Clin Chem 62:123–149

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Zeynep Yuruk Yildirim.

Ethics declarations

This study was approved by the local ethics committee (2012/887-1083). Informed consent was obtained from parents of all children participating in the study.

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The authors declare that they have no conflict of interest.

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Yilmaz, A., Yildirim, Z.Y., Emre, S. et al. Urine heat shock protein 70 levels as a marker of urinary tract infection in children. Pediatr Nephrol 31, 1469–1476 (2016). https://doi.org/10.1007/s00467-016-3361-1

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Keywords

  • Urine heat shock proteins
  • Urinary tract infection
  • Children
  • Biomarker
  • HSP