Abstract
Neutrophil gelatinase-associated lipocalin (NGAL) is a small 25-kD peptide belonging to the lipocalin superfamily. It mainly binds to siderophores, iron-carrying molecules which are essential to bacterial and eukaryotic cells to meet their needs of this mineral and then ensure survival. Indeed, NGAL primarily acts as an innate nonspecific antibacterial factor, since it prevents bacteria to internalize iron thus inhibiting their growth. However, serum NGAL levels rise not only in the course of infective processes but also in other pathological conditions, as the result of an increased production and release from several tissues after an injury. Numerous experimental and clinical data support a role for NGAL as a biomarker in nephrology. It has been demonstrated that NGAL predicts the onset of acute kidney injury (AKI), closely correlates with the extent of renal impairment in patients with chronic kidney disease (CKD) irrespective of the underlying renal disease; it is higher in kidney transplant patients who will develop a delayed graft function (DGF) compared to those who will not experience this complication. Furthermore, NGAL predicts CKD progression and may represent a precocious marker of therapeutic response in different clinical situations. A number of studies also established the involvement of this molecule in carcinogenesis and progression of several human tumors, in the regulation of erythropoiesis and in the pathophysiology of cardiovascular diseases. The aim of the present review has been therefore to summarize all the most recent findings concerning the potential use of NGAL as a diagnostic and prognostic marker as well as a marker of therapeutic response in patients with renal diseases.
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Abbreviations
- ADPKD:
-
Autosomal-dominant polycystic kidney disease
- AKI:
-
Acute kidney injury
- CIN:
-
Contrast-induced nephropathy
- CKD:
-
Chronic kidney disease
- CPB:
-
Cardiopulmonary bypass
- CT:
-
Computed tomography
- DGF:
-
Delayed graft function
- ESRD:
-
End-stage renal disease
- FABP:
-
Fatty acid-binding protein
- FeNGAL:
-
Fractional excretion of NGAL
- GFR:
-
Glomerular filtration rate
- KIM-1:
-
Kidney injury molecule-1
- NAG:
-
N-acetyl-β-d-glucosaminidase
- NGAL:
-
Neutrophil gelatinase-associated lipocalin
- PCI:
-
Percutaneous coronary intervention
- shRNA:
-
Short hairpin RNA
- sNGAL:
-
Serum NGAL
- uNGAL:
-
Urinary NGAL
References
Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17(11):2974–84.
Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol. 2006;26(3):287–92.
Barresi V, Ieni A, Bolignano D, Magno C, Buemi M, Barresi G. Neutrophil gelatinase-associated lipocalin immunoexpression in renal tumors: correlation with histotype and histological grade. Oncol Rep. 2010;24(2):305–10.
Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol. 2008;3(3):665–73.
Bolignano D, Buemi M. Neutrophil Gelatinase-Associated Lipocalin (NGAL): un biomarker oltre i confini della nefrologia. Castrolibero: Nuova Editoriale Bios; 2009.
Bolignano D, Coppolino G, Campo S, et al. Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease. Am J Nephrol. 2007;27(4):373–8.
Bolignano D, Donato V, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008a;52(3):595–605.
Bolignano D, Lacquaniti A, Coppolino G, Campo S, Arena A, Buemi M. Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press Res. 2008b;31:255–8.
Bolignano D, Coppolino G, Lacquaniti A, Nicocia G, Buemi M. Pathological and prognostic value of Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) in macroproteinuric patients with worsening renal function. Kidney Blood Press Res. 2008c;31:274–9.
Bolignano D, Coppolino G, Aloisi C, Romeo A, Nicocia G, Buemi M. Effect of a single intravenous immunoglobulin infusion on neutrophil gelatinase-associated lipocalin levels in proteinuric patients with normal renal function. J Investig Med. 2008d;56(8):997–1003.
Bolignano D, Coppolino G, Campo S, et al. Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant. 2008e;23(1):414–6.
Bolignano D, Coppolino G, Lacquaniti A, Buemi M. Neutrophil gelatinase-associated lipocalin in the intensive care unit: time to look beyond a single, threshold-based measurement? Crit Care Med. 2009a;37(10):2864. author reply 2864–2865.
Bolignano D, Lacquaniti A, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin as an early biomarker of nephropathy in diabetic patients. Kidney Blood Press Res. 2009b;32(2):91–8.
Bolignano D, Coppolino G, Lombardi L, Buemi M. NGAL: a new missing link between inflammation and uremic anemia? Ren Fail. 2009c;31(7):622–3.
Bolignano D, Coppolino G, Romeo A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) reflects iron status in hemodialysis patients. Nephrol Dial Transplant. 2009d;24(11): 3398–403.
Bolignano D, Lacquaniti A, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009e;4(2):337–44.
Bolignano D, Coppolino G, Romeo A, Lacquaniti A, Buemi A. Neutrophil gelatinase- associated lipocalin (NGAL) levels in chronic hemodialysis patients. Nephrology (Carlton). 2010a;15(1):23–6.
Bolignano D, Della Torre A, Lacquaniti A, Costantino G, Fries W, Buemi M. Neutrophil gelatinase-associated lipocalin levels in patients with crohn disease undergoing treatment with infliximab. J Investig Med. 2010b;58(3):569–71.
Bolignano D, Coppolino G, Lacquaniti A, Buemi M. From kidney to cardiovascular diseases: NGAL as a biomarker beyond the confines of nephrology. Eur J Clin Invest. 2010c;40(3):273–6.
Bolignano D, Donato V, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett. 2010d;288(1):10–6.
Bolignano D, Coppolino G, Donato V, Lacquaniti A, Bono C, Buemi M. Neutrophil gelatinase-associated lipocalin (NGAL): a new piece of the anemia puzzle? Med Sci Monit. 2010e;16(6):RA131–5.
Brunner HI, Mueller M, Rutherford C, et al. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2577–84.
Buemi A, Musuamba F, Frederic S, et al. Is plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) determination in donors and recipients predictive of renal function after kidney transplantation? Clin Biochem. 2014;47(15):68–72.
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(12):2229–35.
Cernaro V, Bolignano D, Donato V, et al. NGAL is a precocious marker of therapeutic response. Curr Pharm Des. 2011;17(8):844–9.
Christensen EI, Gburek J. Protein reabsorption in renal proximal tubule-function and dysfunction in kidney pathophysiology. Pediatr Nephrol. 2004;19(7):714–21.
Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics. 1997;45(1):17–23.
Cowland JB, Sørensen OE, Sehested M, Borregaard N. Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol. 2003;171(12):6630–9.
Dent CL, Ma Q, Dastrala S, et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care. 2007;11(6):R127.
Devarajan P. Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology (Carlton). 2010;15(4):419–28.
Devireddy LR, Gazin C, Zhu X, Green MR. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005;123(7):1293–305.
Ding H, He Y, Li K, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol. 2007;123(2):227–34.
Flower DR. The lipocalin protein family: structure and function. Biochem J. 1996;318(Pt 1):1–14.
Goetz DH, Willie ST, Armen RS, Bratt T, Borregaard N, Strong RK. Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin. Biochemistry. 2000;39(8):1935–41.
Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG. Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem. 2005;280(9):7875–82.
Haase-Fielitz A, Bellomo R, Devarajan P, et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery – a prospective cohort study. Crit Care Med. 2009a;37(2):553–60.
Haase-Fielitz A, Bellomo R, Devarajan P, et al. The predictive performance of plasma neutrophil gelatinase-associated lipocalin (NGAL) increases with grade of acute kidney injury. Nephrol Dial Transplant. 2009b;24(11):3349–54.
Han WK, Wagener G, Zhu Y, Wang S, Lee HT. Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol. 2009;4(5):873–82.
Helanova K, Spinar J, Parenica J. Diagnostic and prognostic utility of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in patients with cardiovascular diseases – review. Kidney Blood Press Res. 2014;39(6):623–9.
Hemdahl AL, Gabrielsen A, Zhu C, et al. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol. 2006;26(1):136–42.
Hirsch R, Dent C, Pfriem H, et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol. 2007;22(12):2089–95.
Hraba-Renevey S, Türler H, Kress M, Salomon C, Weil R. SV40-induced expression of mouse gene 24p3 involves a post-transcriptional mechanism. Oncogene. 1989;4(5):601–8.
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(3):773–7.
Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 1993;268(14):10425–32.
Kjeldsen L, Cowland JB, Borregaard N. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochim Biophys Acta. 2000;1482(1–2):272–83.
Kusaka M, Kuroyanagi Y, Mori T, et al. Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death. Cell Transplant. 2008;17(1–2):129–34.
Lacquaniti A, Chirico V, Donato V, et al. NGAL as an early biomarker of kidney disease in Joubert syndrome: three brothers compared. Ren Fail. 2012;34(4):495–8.
Lacquaniti A, Buemi F, Lupica R, et al. Can neutrophil gelatinase-associated lipocalin help depict early contrast material-induced nephropathy? Radiology. 2013;267(1):86–93.
Lebkowska U, Malyszko J, Lebkowska A, et al. Neutrophil gelatinase-associated lipocalin and cystatin C could predict renal outcome in patients undergoing kidney allograft transplantation: a prospective study. Transplant Proc. 2009;41(1):154–7.
Leheste JR, Rolinski B, Vorum H, et al. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol. 1999;155(4):1361–70.
Lin HY, Hwang DY, Lee SC, et al. Urinary neutrophil gelatinase-associated lipocalin and clinical outcomes in chronic kidney disease patients. Clin Chem Lab Med. 2015;53(1):73–83.
Ling W, Zhaohui N, Ben H, et al. Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography. Nephron Clin Pract. 2008;108(3):c176–81.
Lippi G, Meschi T, Nouvenne A, Mattiuzzi C, Borghi L. Neutrophil gelatinase-associated lipocalin in cancer. Adv Clin Chem. 2014;64:179–219.
Makris K, Markou N, Evodia E, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin Chem Lab Med. 2009;47(1):79–82.
Malyszko J, Tesar V, Macdougall IC. Neutrophil gelatinase-associated lipocalin and hepcidin: what do they have in common and is there a potential interaction? Kidney Blood Press Res. 2010;33(2):157–65.
Mårtensson J, Bellomo R. The rise and fall of NGAL in acute kidney injury. Blood Purif. 2014;37(4):304–10.
Meheus LA, Fransen LM, Raymackers JG, et al. Identification by microsequencing of lipopolysaccharide-induced proteins secreted by mouse macrophages. J Immunol. 1993;151(3):1535–47.
Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231–8.
Mishra J, Ma Q, Kelly C, et al. Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol. 2006;21(6):856–63.
Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 2007;71(10):967–70.
Morita Y, Ikeguchi H, Nakamura J, Hotta N, Yuzawa Y, Matsuo S. Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol. 2000;11(4):700–7.
Parikh CR, Jani A, Mishra J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant. 2006;6(7):1639–45.
Playford RJ, Belo A, Poulsom R, et al. Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair. Gastroenterology. 2006;131(3):809–17.
Ronco C, Legrand M, Goldstein SL, et al. Neutrophil gelatinase-associated lipocalin: ready for routine clinical use? An international perspective. Blood Purif. 2014;37(4):271–85.
Santoro D, Pellicanò V, Visconti L, et al. An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease. Expert Opin Investig Drugs. 2015;24:1199–218. Jun 30:1–20.
Schaub S, Mayr M, Hönger G, et al. Detection of subclinical tubular injury after renal transplantation: comparison of urine protein analysis with allograft histopathology. Transplantation. 2007;84(1):104–12.
Schmidt-Ott KM, Mori K, Li JY, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2007;18(2):407–13.
Thomas MC, Burns WC, Cooper ME. Tubular changes in early diabetic nephropathy. Adv Chron Kidney Dis. 2005;12(2):177–86.
van Timmeren MM, Bakker SJ, Vaidya VS, et al. Tubular kidney injury molecule-1 in protein-overload nephropathy. Am J Physiol Renal Physiol. 2006;291(2):F456–64.
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(3):425–33.
Wei F, Karihaloo A, Yu Z, et al. Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo. Kidney Int. 2008;74(10):1310–8.
Yan L, Borregaard N, Kjeldsen L, Moses MA. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem. 2001;276(40):37258–65.
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Cernaro, V., Bolignano, D., Buemi, A., Lacquaniti, A., Santoro, D., Buemi, M. (2016). Overview of Neutrophil Gelatinase-Associated Lipocalin (NGAL) as a Biomarker in Nephrology. In: Patel, V., Preedy, V. (eds) Biomarkers in Kidney Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7699-9_16
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