For many years, neutrophil gelatinase-associated lipocalin (NGAL) has been considered the most promising biomarker of acute kidney injury (AKI). Commercial assays and point-of-care instruments, now available in many hospitals, allow rapid NGAL measurements intended to guide the clinician in the management of patients with or at risk of AKI. However, these assays likely measure a mixture of different NGAL forms originating from different tissues. Systemic inflammation, commonly seen in critically ill patients, and several comorbidities contribute to the release of NGAL from haematopoietic and non-haematopoietic cells. The unpredictable release and complex nature of the molecule and the inability to specifically measure NGAL released by tubular cells have hampered its use a specific marker of AKI in heterogeneous critically ill populations. In this review, we describe the nature and cellular sources of NGAL, its biological role and diagnostic ability in AKI and the increasing concerns surrounding its diagnostic and clinical value.

Keywords:
Neutrophil gelatinase-associated lipocalin, Acute kidney injury, Intensive care, Inflammation
1.
Mishra J, Ma Q, Prada A, et al: Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534-2543.
2.
Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 2004;24:307-315.
3.
Mishra J, Dent C, Tarabishi R, et al: Neutrophil gelatinase-associated lipocalin as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231-1238.
4.
Devarajan P: Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology (Carlton) 2010;15:419-428.
5.
Akcay A, Nguyen Q, Edelstein CL: Mediators of inflammation in acute kidney injury. Mediators Inflamm 2009;2009:137072.
6.
Cowland JB, Borregaard N: Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 1997;45:17-23.
7.
Cai L, Rubin J, Han W, Venge P, Xu S: The origin of multiple molecular forms in urine of HNL/NGAL. Clin J Am Soc Nephrol 2010;5:2229-2235.
8.
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N: Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993;268:10425-10432.
9.
Xu SY, Carlson M, Engstrom A, Garcia R, Peterson CG, Venge P: Purification and characterization of a human neutrophil lipocalin from the secondary granules of human neutrophils. Scand J Clin Lab Invest 1994;54:365-376.
10.
Borregaard N, Cowland JB: Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 1997;89:3503-3521.
11.
Cowland JB, Sorensen OE, Sehested M, Borregaard N: Neutrophil gelatinase-associated lipocalin is upregulated in human epithelial cells by IL-1β, but not by TNF-α. J Immunol 2003;171:6630-6639.
12.
Xu S, Venge P: Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482:298-307.
13.
Xu SY, Pauksen K, Venge P: Serum measurements of human neutrophil lipocalin discriminate between acute bacterial and viral infections. Scand J Clin Lab Invest 1995;55:125-131.
14.
Fjaertoft G, Foucard T, Xu S, Venge P: Human neutrophil lipocalin as a diagnostic tool in children with acute infections: a study of the kinetics. Acta Paediatr 2005;94:661-666.
15.
Martensson J, Xu S, Bell M, Martling CR, Venge P: Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils. Clin Chim Acta 2012;413:1661-1667.
16.
Schmidt-Ott KM, Mori K, Li JY, et al: Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007;18:407-413.
17.
Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK: The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 2002;10:1033-1043.
18.
Flo TH, Smith KD, Sato S, et al: Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004;432:917-921.
19.
Yang J, Goetz D, Li JY, et al: An iron delivery pathway mediated by a lipocalin. Mol Cell 2002;10:1045-1056.
20.
Mishra J, Mori K, Ma Q, et al: Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004;15:3073-3082.
21.
Mori K, Lee HT, Rapoport D, et al: Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005;115:610-621.
22.
Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P: Differential gene expression following early renal ischemia/reperfusion. Kidney Int 2003;63:1714-1724.
23.
Zappitelli M, Washburn KK, Arikan AA, et al: Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 2007;11:R84.
24.
Koyner JL, Vaidya VS, Bennett MR, et al: Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 2010;5:2154-2165.
25.
de Geus HR, Bakker J, Lesaffre EM, Le Noble JL: Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in adult patients. Am J Respir Crit Care Med 2011;183:907-914.
26.
Kashani K, Al-Khafaji A, Ardiles T, et al: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25.
27.
Haase M, Bellomo R, Devarajan P, et al: Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults. Ann Thorac Surg 2009;88:124-130.
28.
Wagener G, Jan M, Kim M, et al: Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485-491.
29.
Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M, Lee HT: Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery. Am J Kidney Dis 2008;52:425-433.
30.
Xin C, Yulong X, Yu C, Changchun C, Feng Z, Xinwei M: Urine neutrophil gelatinase-associated lipocalin and interleukin-18 predict acute kidney injury after cardiac surgery. Ren Fail 2008;30:904-913.
31.
Liangos O, Tighiouart H, Perianayagam MC, et al: Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 2009;14:423-431.
32.
Che M, Xie B, Xue S, et al: Clinical usefulness of novel biomarkers for the detection of acute kidney injury following elective cardiac surgery. Nephron Clin Pract 2010;115:c66-c72.
33.
Parikh CR, Coca SG, Thiessen-Philbrook H, et al: Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J Am Soc Nephrol 2011;22:1748-1757.
34.
Heise D, Rentsch K, Braeuer A, Friedrich M, Quintel M: Comparison of urinary neutrophil glucosaminidase-associated lipocalin, cystatin C, and α1-microglobulin for early detection of acute renal injury after cardiac surgery. Eur J Cardiothorac Surg 2011;39:38-43.
35.
Makris K, Markou N, Evodia E, et al: Urinary neutrophil gelatinase-associated lipocalin as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin Chem Lab Med 2009;47:79-82.
36.
Siew ED, Ware LB, Gebretsadik T, et al: Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults. J Am Soc Nephrol 2009;20:1823-1832.
37.
Martensson J, Bell M, Oldner A, Xu S, Venge P, Martling CR: Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury. Intensive Care Med 2010;36:1333-1340.
38.
Metzger J, Kirsch T, Schiffer E, et al: Urinary excretion of twenty peptides forms an early and accurate diagnostic pattern of acute kidney injury. Kidney Int 2010;78:1252-1262.
39.
Endre ZH, Pickering JW, Walker RJ, et al: Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int 2011;79;1119-1130.
40.
de Geus HR, Fortrie G, Betjes MG, Van Schaik RH, Groeneveld AB: Time of injury affects urinary biomarker predictive values for acute kidney injury in critically ill, non-septic patients. BMC Nephrol 2013;14:273.
41.
Koyner JL, Garg AX, Coca SG, et al: Biomarkers predict progression of acute kidney injury after cardiac surgery. J Am Soc Nephrol 2012;23:905-914.
42.
Puthucheary ZA, Rawal J, McPhail M, et al: Acute skeletal muscle wasting in critical illness. JAMA 2013;310:1591-1600.
43.
Liu KD, Thompson BT, Ancukiewicz M, et al: Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med 2011;39:2665-2671.
44.
Haase M, Devarajan P, Haase-Fielitz A, et al: The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011;57:1752-1761.
45.
Nickolas TL, Schmidt-Ott KM, Canetta P, et al: Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol 2012;59:246-255.
46.
Mitsnefes MM, Kathman TS, Mishra J, et al: Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease. Pediatr Nephrol 2007;22:101-108.
47.
Bolignano D, Lacquaniti A, Coppolino G, et al: Neutrophil gelatinase-associated lipocalin and progression of chronic kidney disease. Clin J Am Soc Nephrol 2009;4:337-344.
48.
McIlroy DR, Wagener G, Lee HT: Neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery: the effect of baseline renal function on diagnostic performance. Clin J Am Soc Nephrol 2010;5:211-219.
49.
Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A: Accuracy of neutrophil gelatinase-associated lipocalin in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009;54:1012-1024.
50.
Uchino S, Kellum JA, Bellomo R, et al: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-818.
51.
Grigoryev DN, Liu M, Hassoun HT, Cheadle C, Barnes KC, Rabb H: The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol 2008;19:547-558.
52.
Koyner JL, Bennett MR, Worcester EM, et al: Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery. Kidney Int 2008;74:1059-1069.
53.
Cai L, Borowiec J, Xu S, Han W, Venge P: 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 2009;403:121-125.
54.
Martensson J, Bell M, Xu S, et al: Association of plasma neutrophil gelatinase-associated lipocalin with sepsis and acute kidney dysfunction. Biomarkers 2013;18:349-356.
55.
Nickolas TL, O'Rourke MJ, Yang J, et al: Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 2008;148:810-819.
56.
Shapiro NI, Trzeciak S, Hollander JE, et al: 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 2010;56:52-59 e51.
57.
Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N: The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 2005;579:773-777.
58.
Kuwabara T, Mori K, Mukoyama M, et al: Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int 2009;75:285-294.
59.
Awad AS, Rouse M, Huang L, et al: Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int 2009;75:689-698.
60.
Lerolle N, Nochy D, Guerot E, et al: Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 2010;36:471-478.
61.
Glassford NJ, Schneider AG, Xu S, et al: The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury. Intensive Care Med 2013;39:1714-1724.
62.
Åberg A: Myocardial Infarctions in Sweden 1987-2005. Stockholm, Official Statistics of Sweden, 2008, pp 1-102.
63.
Mahadavan G, Nguyen TH, Horowitz JD: Brain natriuretic peptide: a biomarker for all cardiac disease? Curr Opin Cardiol 2014;29:160-166.
64.
Mercier E, Boutin A, Lauzier F, et al: Predictive value of S-100β protein for prognosis in patients with moderate and severe traumatic brain injury: systematic review and meta-analysis. BMJ 2013;346:f1757.
65.
Taccone FS, Cronberg T, Friberg H, et al: How to assess prognosis after cardiac arrest and therapeutic hypothermia. Crit Care 2014;18:202.
66.
Markou N, Gregorakos L, Myrianthefs P: Increased blood troponin levels in ICU patients. Curr Opin Crit Care 2011;17:454-463.
67.
Noveanu M, Mebazaa A, Mueller C: Cardiovascular biomarkers in the ICU. Curr Opin Crit Care 2009;15:377-383.
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2014
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