Intensive Care Medicine

, Volume 39, Issue 10, pp 1714–1724 | Cite as

The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury

  • Neil J. Glassford
  • Antoine G. Schneider
  • Shengyuan Xu
  • Glenn M. Eastwood
  • Helen Young
  • Leah Peck
  • Per Venge
  • Rinaldo Bellomo
Seven-Day Profile Publication

Abstract

Background

Different molecular forms of urinary neutrophil gelatinase-associated lipocalin (NGAL) have recently been discovered. We aimed to explore the nature, source and discriminatory value of urinary NGAL in intensive care unit (ICU) patients.

Methods

We simultaneously measured plasma NGAL (pNGAL), urinary NGAL (uNGAL), and estimated monomeric and homodimeric uNGAL contribution using Western blotting-validated enzyme-linked immunosorbent assays [uNGALE1 and uNGALE2] and their calculated ratio in 102 patients with the systemic inflammatory response syndrome and oliguria, and/or a creatinine rise of >25 μmol/L.

Measurements and main results

Bland–Altman analysis demonstrated that, despite correlating well (r = 0.988), uNGAL and uNGALE1 were clinically distinct, lacking both accuracy and precision (bias: 266.23; 95 % CI 82.03–450.44 ng/mg creatinine; limits of agreement: −1,573.86 to 2,106.32 ng/mg creatinine). At best, urinary forms of NGAL are fair (area under the receiver operating characteristic [AUROC] ≤0.799) predictors of renal or patient outcome; most perform significantly worse. The 44 patients with a primarily monomeric source of uNGAL had higher pNGAL (118.5 ng/ml vs. 72.5 ng/ml; p < 0.001), remaining significant following Bonferroni correction.

Conclusions

uNGAL is not a useful predictor of outcome in this ICU population. uNGAL patterns may predict distinct clinical phenotypes. The nature and source of uNGAL are complex and challenge the utility of NGAL as a uniform biomarker.

Keywords

Acute kidney injury Oliguria Critical illness Intensive care Biomarker Systemic inflammatory response syndrome 

Notes

Acknowledgments

This study was supported by the Austin Hospital Intensive Care Trust Fund. The ELISA testing was funded by a grant from the Swedish Medical Research Council to Uppsala University.

Conflicts of interest

Shengyuan Xu holds patents with, and receives royalties from, Diagnostics Development. Per Venge holds patents with, and stock in, P&M Venge AB. He has received royalties from Phadia. The remaining authors declare that they have no conflicts of interest.

Supplementary material

134_2013_3040_MOESM1_ESM.docx (91 kb)
Supplementary material 1 (DOCX 90 kb)

References

  1. 1.
    Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365:1231–1238PubMedCrossRefGoogle Scholar
  2. 2.
    Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14:2534–2543PubMedCrossRefGoogle Scholar
  3. 3.
    Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J (2008) Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 148:810–819PubMedCrossRefGoogle Scholar
  4. 4.
    Bagshaw SM (2011) Subclinical acute kidney injury: a novel biomarker-defined syndrome. Crit Care Resusc 13:201–203PubMedGoogle Scholar
  5. 5.
    Legrand M, Collet C, Gayat E, Henao J, Giraudeaux V, Mateo J, Launay JM, Payen D (2013) Accuracy of urine NGAL commercial assays in critically ill patients. Intensive Care Med 39:541–542PubMedCrossRefGoogle Scholar
  6. 6.
    Zhang X, Gibson B Jr, Mori R, Snow-Lisy D, Yamaguchi Y, Campbell SC, Simmons MN, Daly TM (2012) Analytical and biological validation of a multiplex immunoassay for acute kidney injury biomarkers. Clin Chim Acta 415C:88–93Google Scholar
  7. 7.
    Xu SY, Petersson CG, Carlson M, Venge P (1994) The development of an assay for human neutrophil lipocalin (HNL)—to be used as a specific marker of neutrophil activity in vivo and vitro. J Immunol Methods 171:245–252PubMedCrossRefGoogle Scholar
  8. 8.
    Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, Devarajan P (2007) Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 11:R127PubMedCrossRefGoogle Scholar
  9. 9.
    Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S, Barasch J, Devarajan P (2008) Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol 3:665–673PubMedCrossRefGoogle Scholar
  10. 10.
    Xu SY, Carlson M, Engstrom A, Garcia R, Peterson CG, Venge P (1994) Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand J Clin Lab Invest 54:365–376PubMedCrossRefGoogle Scholar
  11. 11.
    Carlson M, Raab Y, Seveus L, Xu S, Hallgren R, Venge P (2002) Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis. Gut 50:501–506PubMedCrossRefGoogle Scholar
  12. 12.
    Cowland JB, Borregaard N (1997) Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 45:17–23PubMedCrossRefGoogle Scholar
  13. 13.
    Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A (2008) Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat 108:389–397PubMedCrossRefGoogle Scholar
  14. 14.
    Cowland JB, Sorensen OE, Sehested M, Borregaard N (2003) Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol 171:6630–6639PubMedGoogle Scholar
  15. 15.
    Nielsen BS, Borregaard N, Bundgaard JR, Timshel S, Sehested M, Kjeldsen L (1996) Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut 38:414–420PubMedCrossRefGoogle Scholar
  16. 16.
    Roudkenar MH, Kuwahara Y, Baba T, Roushandeh AM, Ebishima S, Abe S, Ohkubo Y, Fukumoto M (2007) Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. J Radiat Res 48:39–44PubMedCrossRefGoogle Scholar
  17. 17.
    Cai L, Rubin J, Han W, Venge P, Xu S (2010) The origin of multiple molecular forms in urine of HNL/NGAL. Clin J Am Soc Nephrol 5:2229–2235PubMedCrossRefGoogle Scholar
  18. 18.
    Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432PubMedGoogle Scholar
  19. 19.
    Blaser J, Triebel S, Tschesche H (1995) A sandwich enzyme immunoassay for the determination of neutrophil lipocalin in body fluids. Clin Chim Acta 235:137–145PubMedCrossRefGoogle Scholar
  20. 20.
    Kjeldsen L, Koch C, Arnljots K, Borregaard N (1996) Characterization of two ELISAs for NGAL, a newly described lipocalin in human neutrophils. J Immunol Methods 198:155–164PubMedCrossRefGoogle Scholar
  21. 21.
    Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24:307–315PubMedCrossRefGoogle Scholar
  22. 22.
    Cai L, Borowiec J, Xu S, Han W, Venge P (2009) Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances. Clin Chim Acta 403:121–125PubMedCrossRefGoogle Scholar
  23. 23.
    Martensson J, Xu S, Bell M, Martling CR, Venge P (2012) Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils. Clin Chim Acta 413:1661–1667PubMedCrossRefGoogle Scholar
  24. 24.
    Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34:17–60PubMedCrossRefGoogle Scholar
  25. 25.
    Zavada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, Bellomo R, Kellum JA (2010) A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transpl 25:3911–3918CrossRefGoogle Scholar
  26. 26.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212PubMedCrossRefGoogle Scholar
  27. 27.
    Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, Sirio CA, Murphy DJ, Lotring T, Damiano A et al (1991) The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 100:1619–1636PubMedCrossRefGoogle Scholar
  28. 28.
    Calzavacca P, Tee A, Licari E, Schneider AG, Bellomo R (2012) Point-of-care measurement of serum creatinine in the intensive care unit. Ren Fail 34:13–18PubMedCrossRefGoogle Scholar
  29. 29.
    Taylor R (1990) Interpretation of the correlation coefficient: a basic review. J Diagn Med Sonogr 1:35–39CrossRefGoogle Scholar
  30. 30.
    Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307–310PubMedCrossRefGoogle Scholar
  31. 31.
    Mantha S, Roizen MF, Fleisher LA, Thisted R, Foss J (2000) Comparing methods of clinical measurement: reporting standards for bland and altman analysis. Anesth Analg 90:593–602PubMedCrossRefGoogle Scholar
  32. 32.
    Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8:135–160PubMedCrossRefGoogle Scholar
  33. 33.
    Haase-Fielitz A, Bellomo R, Devarajan P, Story D, Matalanis G, Dragun D, Haase M (2009) Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery: a prospective cohort study. Crit Care Med 37:553–560PubMedCrossRefGoogle Scholar
  34. 34.
    Krawczeski CD, Goldstein SL, Woo JG, Wang Y, Piyaphanee N, Ma Q, Bennett M, Devarajan P (2011) Temporal relationship and predictive value of urinary acute kidney injury biomarkers after pediatric cardiopulmonary bypass. J Am Coll Cardiol 58:2301–2309PubMedCrossRefGoogle Scholar
  35. 35.
    Tuladhar SM, Puntmann VO, Soni M, Punjabi PP, Bogle RG (2009) Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass. J Cardiovasc Pharmacol 53:261–266PubMedCrossRefGoogle Scholar
  36. 36.
    Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M, Lee HT (2008) Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery. Am J Kidney Dis 52:425–433PubMedCrossRefGoogle Scholar
  37. 37.
    Xin C, Yulong X, Yu C, Changchun C, Feng Z, Xinwei M (2008) Urine neutrophil gelatinase-associated lipocalin and interleukin-18 predict acute kidney injury after cardiac surgery. Ren Fail 30:904–913PubMedCrossRefGoogle Scholar
  38. 38.
    Shapiro NI, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Osborn TM, Moretti E, Nguyen HB, Gunnerson K, Milzman D, Gaieski DF, Goyal M, Cairns CB, Kupfer K, Lee SW, Rivers EP (2010) The diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin in the prediction of acute kidney injury in emergency department patients with suspected sepsis. Ann Emerg Med 56(52–59):e51Google Scholar
  39. 39.
    Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A (2009) Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 54:1012–1024PubMedCrossRefGoogle Scholar
  40. 40.
    Bagshaw SM, Bennett M, Haase M, Haase-Fielitz A, Egi M, Morimatsu H, D’Amico G, Goldsmith D, Devarajan P, Bellomo R (2010) Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 36:452–461PubMedCrossRefGoogle Scholar
  41. 41.
    de Geus HR, Bakker J, Lesaffre EM, le Noble JL (2011) Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in adult patients. Am J Respir Crit Care Med 183:907–914PubMedCrossRefGoogle Scholar
  42. 42.
    Doi K, Negishi K, Ishizu T, Katagiri D, Fujita T, Matsubara T, Yahagi N, Sugaya T, Noiri E (2011) Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit. Crit Care Med 39:2464–2469PubMedCrossRefGoogle Scholar
  43. 43.
    Endre ZH, Pickering JW, Walker RJ, Devarajan P, Edelstein CL, Bonventre JV, Frampton CM, Bennett MR, Ma Q, Sabbisetti VS, Vaidya VS, Walcher AM, Shaw GM, Henderson SJ, Nejat M, Schollum JB, George PM (2011) Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int 79:1119–1130PubMedCrossRefGoogle Scholar
  44. 44.
    Kokkoris S, Parisi M, Ioannidou S, Douka E, Pipili C, Kyprianou T, Kotanidou A, Nanas S (2012) Combination of renal biomarkers predicts acute kidney injury in critically ill adults. Ren Fail 34:1100–1108PubMedCrossRefGoogle Scholar
  45. 45.
    Martensson J, Bell M, Oldner A, Xu S, Venge P, Martling CR (2010) Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury. Intensive Care Med 36:1333–1340PubMedCrossRefGoogle Scholar
  46. 46.
    Siew ED, Ware LB, Gebretsadik T, Shintani A, Moons KG, Wickersham N, Bossert F, Ikizler TA (2009) Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults. J Am Soc Nephrol 20:1823–1832PubMedCrossRefGoogle Scholar
  47. 47.
    Royakkers AA, Bouman CS, Stassen PM, Korevaar JC, Binnekade JM, van de Hoek W, Kuiper MA, Spronk PE, Schultz MJ (2012) Systemic and urinary neutrophil gelatinase-associated lipocalins are poor predictors of acute kidney injury in unselected critically ill patients. Crit Care Res Pract 2012:712695PubMedGoogle Scholar
  48. 48.
    Cruz DN, de Cal M, Garzotto F, Perazella MA, Lentini P, Corradi V, Piccinni P, Ronco C (2010) Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med 36:444–451PubMedCrossRefGoogle Scholar
  49. 49.
    Constantin JM, Futier E, Perbet S, Roszyk L, Lautrette A, Gillart T, Guerin R, Jabaudon M, Souweine B, Bazin JE, Sapin V (2010) Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study. J Crit Care 25(176):e171–e176Google Scholar
  50. 50.
    Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W (2012) Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. Nephrol Dial Transpl 28(2):254–273CrossRefGoogle Scholar
  51. 51.
    Grenier FC, Ali S, Syed H, Workman R, Martens F, Liao M, Wang Y, Wong PY (2010) Evaluation of the ARCHITECT urine NGAL assay: assay performance, specimen handling requirements and biological variability. Clin Biochem 43:615–620PubMedCrossRefGoogle Scholar
  52. 52.
    Haase M, Haase-Fielitz A, Bellomo R, Mertens PR, (2010) Neutrophil gelatinase-associated lipocalin as a marker of acute renal disease. Curr Opin HematolGoogle Scholar
  53. 53.
    Vaidya VS, Waikar SS, Ferguson MA, Collings FB, Sunderland K, Gioules C, Bradwin G, Matsouaka R, Betensky RA, Curhan GC, Bonventre JV (2008) Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci 1:200–208PubMedCrossRefGoogle Scholar
  54. 54.
    Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138CrossRefGoogle Scholar
  55. 55.
    Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M (2004) Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 15:1597–1605PubMedCrossRefGoogle Scholar
  56. 56.
    Levy MM, Macias WL, Vincent JL, Russell JA, Silva E, Trzaskoma B, Williams MD (2005) Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 33:2194–2201PubMedCrossRefGoogle Scholar
  57. 57.
    Praught ML, Shlipak MG (2005) Are small changes in serum creatinine an important risk factor? Curr Opin Nephrol Hypertens 14:265–270PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2013

Authors and Affiliations

  • Neil J. Glassford
    • 1
  • Antoine G. Schneider
    • 1
  • Shengyuan Xu
    • 2
  • Glenn M. Eastwood
    • 1
  • Helen Young
    • 1
  • Leah Peck
    • 1
  • Per Venge
    • 2
  • Rinaldo Bellomo
    • 1
    • 3
  1. 1.Department of Intensive CareAustin HospitalMelbourneAustralia
  2. 2.Department of Medical Sciences, Clinical ChemistryUppsala UniversityUppsalaSweden
  3. 3.Australian and New Zealand Intensive Care Research Centre and Department of Epidemiology and Preventive MedicineMonash UniversityMelbourneAustralia

Personalised recommendations