Pediatric Nephrology

, Volume 28, Issue 1, pp 135–144 | Cite as

Impact of sepsis on the urinary level of interleukin-18 and cystatin C in critically ill neonates

  • Yanhong Li
  • Xiaozhong Li
  • Xiaofei Zhou
  • Jie Yan
  • Xueping Zhu
  • Jian Pan
  • Meifang Jin
  • Xueming Zhu
  • Xing FengEmail author
  • Zhihui XiaoEmail author
Original Article



Urinary interleukin-18 (uIL-18) and cystatin C (uCysC) are biomarkers of acute kidney injury (AKI). We hypothesized that in non-AKI neonates, the level of uIL-18 and uCysC would be higher in those with sepsis compared to those without sepsis. The aims of this study were to determine the association between urinary biomarkers and sepsis in non-AKI critically ill neonates, and to evaluate whether uIL-18 and uCysC could serve as predictors of sepsis in this population.


The study included 111 non-AKI critically ill neonates with acute clinical deterioration suggestive of sepsis: 26 with infection, 57 without infection, and 28 were assigned to the unclassified group. Urinary samples were collected and a full sepsis screen was performed at the time of enrollment.


The level of uIL-18, but not uCysC, was significantly elevated in non-AKI septic neonates. Urinary IL-18 was an independent factor associated with sepsis assessed by multivariate analysis, had odds ratio of 1.73 (95 % CI 1.15 to 2.58, p = 0.008), and achieved the area under the receiver operating characteristic curve of 0.74 for predicting the presence of sepsis in non-AKI critically ill neonates.


Sepsis has an impact on the level of uIL-18, but not on the uCysC in non-AKI neonates, suggesting systemic infection might influence the diagnostic value of uIL-18 to detect AKI in the general population.


Acute kidney injury Critically ill neonates C-reactive protein Diagnostic test Urinary biomarkers Urinary cystatin C Urinary interleukin-18 Sepsis 



Acute kidney injury


Area under the receiver operating characteristic curve




C-reactive protein


Cerebrospinal fluid


Cystatin C




Neonatal intensive care unit


Receiver operating characteristic


The score for neonatal acute physiology



We thank the staff in biochemistry laboratory for technical assistance. This work was supported by grants from the Science and Technology Program of Suzhou (SYS201137).


  1. 1.
    Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N (2009) Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case–control analysis. Pediatr Nephrol 24:991–997PubMedCrossRefGoogle Scholar
  2. 2.
    Askenazi DJ, Ambalavanan N, Goldstein SL (2009) Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol 24:265–274PubMedCrossRefGoogle Scholar
  3. 3.
    Askenazi DJ, Montesanti A, Hunley H, Koralkar R, Pawar P, Shuaib F, Liwo A, Devarajan P, Ambalavanan N (2012) Urine biomarkers predict acute kidney injury and mortality in very low birth weight infants. J Pediatr 159(907–912):e901Google Scholar
  4. 4.
    Li Y, Fu C, Zhou X, Xiao Z, Zhu X, Jin M, Li X, Feng X (2012) Urine interleukin-18 and cystatin C as biomarkers of acute kidney injury in critically ill neonates. Pediatr Nephrol 27:851–860PubMedCrossRefGoogle Scholar
  5. 5.
    Askenazi DJ, Koralkar R, Levitan EB, Goldstein SL, Devarajan P, Khandrika S, Mehta RL, Ambalavanan N (2011) Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants. Pediatr Res 70:302–306PubMedCrossRefGoogle Scholar
  6. 6.
    Nejat M, Pickering JW, Walker RJ, Westhuyzen J, Shaw GM, Frampton CM, Endre ZH (2010) Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit. Crit Care 14:R85PubMedCrossRefGoogle Scholar
  7. 7.
    Royakkers AA, Korevaar JC, van Suijlen JD, Hofstra LS, Kuiper MA, Spronk PE, Schultz MJ, Bouman CS (2011) Serum and urine cystatin C are poor biomarkers for acute kidney injury and renal replacement therapy. Intensive Care Med 37:493–501PubMedCrossRefGoogle Scholar
  8. 8.
    Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL (2005) Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 16:3046–3052PubMedCrossRefGoogle Scholar
  9. 9.
    Haase M, Bellomo R, Story D, Davenport P, Haase-Fielitz A (2008) Urinary interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study. Crit Care 12:R96PubMedCrossRefGoogle Scholar
  10. 10.
    Tschoeke SK, Oberholzer A, Moldawer LL (2006) Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med 34:1225–1233PubMedCrossRefGoogle Scholar
  11. 11.
    Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, Edelstein CL, Goldstein SL (2008) Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant 23:566–572PubMedCrossRefGoogle Scholar
  12. 12.
    Siew ED, Ikizler TA, Gebretsadik T, Shintani A, Wickersham N, Bossert F, Peterson JF, Parikh CR, May AK, Ware LB (2010) Elevated urinary IL-18 levels at the time of ICU admission predict adverse clinical outcomes. Clin J Am Soc Nephrol 5:1497–1505PubMedCrossRefGoogle Scholar
  13. 13.
    Bagshaw SM, Langenberg C, Haase M, Wan L, May CN, Bellomo R (2007) Urinary biomarkers in septic acute kidney injury. Intensive Care Med 33:1285–1296PubMedCrossRefGoogle Scholar
  14. 14.
    Inker LA, Okparavero A (2011) Cystatin C as a marker of glomerular filtration rate: prospects and limitations. Curr Opin Nephrol Hypertens 20:631–639PubMedCrossRefGoogle Scholar
  15. 15.
    Andersen TB, Eskild-Jensen A, Frokiaer J, Brochner-Mortensen J (2009) Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review. Pediatr Nephrol 24:929–941PubMedCrossRefGoogle Scholar
  16. 16.
    Grubb AO (2000) Cystatin C–properties and use as diagnostic marker. Adv Clin Chem 35:63–99PubMedCrossRefGoogle Scholar
  17. 17.
    Herget-Rosenthal S, van Wijk JA, Brocker-Preuss M, Bokenkamp A (2007) Increased urinary cystatin C reflects structural and functional renal tubular impairment independent of glomerular filtration rate. Clin Biochem 40:946–951PubMedCrossRefGoogle Scholar
  18. 18.
    Conti M, Moutereau S, Zater M, Lallali K, Durrbach A, Manivet P, Eschwege P, Loric S (2006) Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med 44:288–291PubMedCrossRefGoogle Scholar
  19. 19.
    Hellerstein S, Berenbom M, Erwin P, Wilson N, DiMaggio S (2004) The ratio of urinary cystatin C to urinary creatinine for detecting decreased GFR. Pediatr Nephrol 19:521–525PubMedCrossRefGoogle Scholar
  20. 20.
    Dorling JS, Field DJ, Manktelow B (2005) Neonatal disease severity scoring systems. Arch Dis Child Fetal Neonatal Ed 90:F11–16PubMedCrossRefGoogle Scholar
  21. 21.
    Kumar D, Super DM, Fajardo RA, Stork EE, Moore JJ, Saker FA (2004) Predicting outcome in neonatal hypoxic respiratory failure with the score for neonatal acute physiology (SNAP) and highest oxygen index (OI) in the first 24 hours of admission. J Perinatol 24:376–381PubMedCrossRefGoogle Scholar
  22. 22.
    Chiesa C, Panero A, Rossi N, Stegagno M, De Giusti M, Osborn JF, Pacifico L (1998) Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis 26:664–672PubMedCrossRefGoogle Scholar
  23. 23.
    Chiesa C, Pellegrini G, Panero A, Osborn JF, Signore F, Assumma M, Pacifico L (2003) C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection. Clin Chem 49:60–68PubMedCrossRefGoogle Scholar
  24. 24.
    Cetinkaya M, Ozkan H, Koksal N, Celebi S, Hacimustafaoglu M (2009) Comparison of serum amyloid A concentrations with those of C-reactive protein and procalcitonin in diagnosis and follow-up of neonatal sepsis in premature infants. J Perinatol 29:225–231PubMedCrossRefGoogle Scholar
  25. 25.
    Dollner H, Vatten L, Austgulen R (2001) Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. J Clin Epidemiol 54:1251–1257PubMedCrossRefGoogle Scholar
  26. 26.
    Murphy K, Weiner J (2012) Use of leukocyte counts in evaluation of early onset neonatal sepsis. Pediatr Infect Dis J 31:16–19PubMedCrossRefGoogle Scholar
  27. 27.
    Hofer N, Zacharias E, Muller W, Resch B (2012) An update on the use of C-reactive protein in early onset neonatal sepsis: current insights and new tasks. Neonatology 102:25–36PubMedCrossRefGoogle Scholar
  28. 28.
    Bhandari V, Wang C, Rinder C, Rinder H (2008) Hematologic profile of sepsis in neonates: neutrophil CD64 as a diagnostic marker. Pediatrics 121:129–134PubMedCrossRefGoogle Scholar
  29. 29.
    Santuz P, Soffiati M, Dorizzi RM, Benedetti M, Zaglia F, Biban P (2008) Procalcitonin for the diagnosis of early onset neonatal sepsis: a multilevel probabilistic approach. Clin Biochem 41:1150–1155PubMedCrossRefGoogle Scholar
  30. 30.
    Zelenina M, Li Y, Glorieux I, Arnaud C, Cristini C, Decramer S, Aperia A, Casper C (2006) Urinary aquaporin-2 excretion during early human development. Pediatr Nephrol 21:947–952PubMedCrossRefGoogle Scholar
  31. 31.
    Li Y, Zelenina M, Plat-Willson G, Marcoux MO, Aperia A, Casper C (2011) Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus. Acta Paediatr 100:59–66PubMedCrossRefGoogle Scholar
  32. 32.
    Jetton JG, Askenazi DJ (2012) Update on acute kidney injury in the neonate. Curr Opin Pediatr 24:191–196PubMedCrossRefGoogle Scholar
  33. 33.
    Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2–8PubMedCrossRefGoogle Scholar
  34. 34.
    Vouloumanou EK, Plessa E, Karageorgopoulos DE, Mantadakis E, Falagas ME (2011) Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and meta-analysis. Intensive Care Med 37:747–762PubMedCrossRefGoogle Scholar
  35. 35.
    Stocker M, Hop WC, van Rossum AM (2010) Neonatal Procalcitonin Intervention Study (NeoPInS): effect of Procalcitonin-guided decision making on duration of antibiotic therapy in suspected neonatal early-onset sepsis: A multi-centre randomized superiority and non-inferiority Intervention Study. BMC Pediatr 10:89PubMedCrossRefGoogle Scholar
  36. 36.
    Ng PC, Lam HS (2006) Diagnostic markers for neonatal sepsis. Curr Opin Pediatr 18:125–131PubMedCrossRefGoogle Scholar
  37. 37.
    Mishra UK, Jacobs SE, Doyle LW, Garland SM (2006) Newer approaches to the diagnosis of early onset neonatal sepsis. Arch Dis Child Fetal Neonatal Ed 91:F208–212PubMedCrossRefGoogle Scholar
  38. 38.
    Polin RA (2012) Management of neonates with suspected or proven early onset bacterial sepsis. Pediatrics 129:1006–1015PubMedCrossRefGoogle Scholar
  39. 39.
    Standage SW, Wong HR (2011) Biomarkers for pediatric sepsis and septic shock. Expert Rev Anti Infect Ther 9:71–79PubMedCrossRefGoogle Scholar
  40. 40.
    Chiesa C, Natale F, Pascone R, Osborn JF, Pacifico L, Bonci E, De Curtis M (2011) C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 412:1053–1059PubMedCrossRefGoogle Scholar
  41. 41.
    Hsu CW, Symons JM (2010) Acute kidney injury: can we improve prognosis? Pediatr Nephrol 25:2401–2412PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  • Yanhong Li
    • 1
    • 2
  • Xiaozhong Li
    • 2
  • Xiaofei Zhou
    • 3
  • Jie Yan
    • 3
  • Xueping Zhu
    • 3
  • Jian Pan
    • 1
  • Meifang Jin
    • 1
  • Xueming Zhu
    • 1
  • Xing Feng
    • 3
    Email author
  • Zhihui Xiao
    • 3
    Email author
  1. 1.Institute of pediatric researchChildren’s Hospital of Soochow UniversitySuzhouChina
  2. 2.Department of nephrologyChildren’s Hospital of Soochow UniversitySuzhouChina
  3. 3.Department of neonatologyChildren’s Hospital of Soochow UniversitySuzhouChina

Personalised recommendations