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Neutrophil Gelatinase-Associated Lipocalin and Kidney Diseases

  • Yim, Hyung Eun (Department of Pediatrics, College of Medicine, Korea University)
  • Received : 2015.09.23
  • Accepted : 2015.10.22
  • Published : 2015.10.30

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as one of the most promising biomarkers of renal epithelial injury. Numerous studies have presented the diagnostic and prognostic utility of urinary and plasma NGAL in patients with acute kidney injury, chronic kidney disease, renal injury after kidney transplantation, and other renal diseases. NGAL is a member of the lipocalin family that is abundantly expressed in neutrophils and monocytes/macrophages and is a mediator of the innate immune response. The biological significance of NGAL to hamper bacterial growth by sequestering iron-binding siderophores has been studied in a knock-out mouse model. Besides neutrophils, NGAL is detectable in most tissues normally encountered by microorganisms, and its expression is upregulated in epithelial cells during inflammation. A growing number of studies have supported the clinical utility of NAGL for detecting invasive bacterial infections. Several investigators including our group have reported that measuring NGAL can be used to help predict and manage urinary tract infections and acute pyelonephritis. This article summarizes the biology and pathophysiology of NGAL and reviews studies on the implications of NGAL in various renal diseases from acute kidney injury to acute pyelonephritis.

Keywords

References

  1. Singer E, Marko L, Paragas N, Barasch J, Dragun D, Muller DN, et al. Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta Physiol (Oxf) 2013;207: 663-72. https://doi.org/10.1111/apha.12054
  2. 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; 268:10425-32.
  3. Lisowska-Myjak B. Serum and urinary biomarkers of acute kidney injury. Blood Purif 2010;29: 357-65. https://doi.org/10.1159/000309421
  4. Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, Paragas N, Nicholas T, et al. Neutrophil gelatinase-associated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol Hypertens. 2006;15:442-9. https://doi.org/10.1097/01.mnh.0000232886.81142.58
  5. Singer E, Elger A, Elitok S, Kettritz R, Nickolas TL, Barasch J, et al. Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes. Kidney Int. 2011;80:405-14. https://doi.org/10.1038/ki.2011.41
  6. Zheng J, Xiao Y, Yao Y, Xu G, Li C, Zhang Q, et al. Comparison of urinary biomarkers for early detection of acute kidney injury after cardiopulmonary bypass surgery in infants and young children. Pediatr Cardiol. 2013;34:880-6. https://doi.org/10.1007/s00246-012-0563-6
  7. Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 2009;4:337-44. https://doi.org/10.2215/CJN.03530708
  8. Hollmen ME, Kyllonen LE, Inkinen KA, Lalla ML, Salmela KT. Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation. Kidney Int 2011;79:89-98. https://doi.org/10.1038/ki.2010.351
  9. Ichino M, Kusaka M, Kuroyanagi Y, Mori T, MorookaM, Sasaki H, et al. Urinary neutrophil-gelatinase associated lipocalin is a potential noninvasive marker for renal scarring in patients with vesicoureteral reflux. J Urol 2010;183:2001-7. https://doi.org/10.1016/j.juro.2010.01.031
  10. Ding H, He Y, Li K, Yang J, Li X, Lu R, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol 2007;123:227-34. https://doi.org/10.1016/j.clim.2007.01.010
  11. Bolignano D, Coppolino G, Lacquaniti A, Nicocia G, Buemi M. Pathological and prognostic value of urinary neutrophil gelatinaseassociated lipocalin (NGAL) in macroproteinuric patients with worsening renal function. Kidney Blood Press Res 2008;31:274-9. https://doi.org/10.1159/000151665
  12. Peters HP, Waanders F, Meijer E, van den Brand J, Steenbergen EJ, van Goor H, et al. High urinary excretion of kidney injury molecule-1 is an independent predictor of end-stage renal disease in patients with IgA nephropathy. Nephrol Dial Transplant 2011;26:3581-8. https://doi.org/10.1093/ndt/gfr135
  13. Wu Y, Su T, Yang L, Zhu SN, Li XM. Urinary neutrophil gelatinaseassociated lipocalin: A potential biomarker for predicting rapid progression of drug-induced chronic tubulointerstitial nephritis. Am J Med Sci 2010;339:537-42. https://doi.org/10.1097/MAJ.0b013e3181dd0cb1
  14. Piccoli GB, Ferraresi M, Aroasio E, Gonella S, De Pascale A, Veltri A. The search for perfect biomarkers in acute kidney damage: the case of NGAL, from AKI to acute pyelonephritis: back to the clinic? Nephrol Dial Transplant 2012;27:3665-6. https://doi.org/10.1093/ndt/gfs331
  15. Yilmaz A, Sevketoglu E, Gedikbasi A, Karyagar S, Kiyak A, Mulazimoglu M, et al. Early prediction of urinary tract infection with urinary neutrophil gelatinase associated lipocalin. Pediatr Nephrol 2009;24:2387-92. https://doi.org/10.1007/s00467-009-1279-6
  16. Seo WH, Nam SW, Lee EH, Je BK, Yim HE, Choi BM. A rapid plasma neutrophil gelatinase-associated lipocalin assay for diagnosis of acute pyelonephritis in infants with acute febrile urinary tract infections: a preliminary study. Eur J Pediatr 2014;173:229-32. https://doi.org/10.1007/s00431-013-2112-6
  17. Yim HE, Yim H, Bae ES, Woo SU, Yoo KH. Predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections. Pediatr Nephrol 2014;29:2181-9. https://doi.org/10.1007/s00467-014-2845-0
  18. Sim JH, Yim HE, Choi BM, Lee JH, Yoo KH. Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections. Pediatr Res 2015;78:48-55. https://doi.org/10.1038/pr.2015.59
  19. Borregaard N, Cowland JB. Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Biometals 2006;19:211-5. https://doi.org/10.1007/s10534-005-3251-7
  20. Devireddy LR, Gazin C, Zhu X, Green MR. A cell surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005;123:1293-305. https://doi.org/10.1016/j.cell.2005.10.027
  21. 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;10:1033-43. https://doi.org/10.1016/S1097-2765(02)00708-6
  22. Berger T, Togawa A, Duncan GS, Elia AJ, You-Ten A, Wakeham A, et al. Lipocalin 2-deficientmice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA 2006;103:1834-9. https://doi.org/10.1073/pnas.0510847103
  23. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004;432:917-21. https://doi.org/10.1038/nature03104
  24. Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, et al. Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007;18:407-13. https://doi.org/10.1681/ASN.2006080882
  25. Yang J, Blum A, Novak T, Levinson R, Lai E, Barasch J. An epithelial precursor is regulated by the ureteric bud and by the renal stroma. Dev Biol 2002;246: 296-310. https://doi.org/10.1006/dbio.2002.0646
  26. 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. https://doi.org/10.1006/geno.1997.4896
  27. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534-43. https://doi.org/10.1097/01.ASN.0000088027.54400.C6
  28. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. https://doi.org/10.1186/cc5713
  29. Clerico A, Galli C, Fortunato A, Ronco C. Neutrophil gelatinaseassociated lipocalin (NGAL) as biomarker of acute kidney injury: a review of the laboratory characteristics and clinical evidences. Clin Chem Lab Med 2012;50:1505-17.
  30. 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;52:425-33. https://doi.org/10.1053/j.ajkd.2008.05.018
  31. Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q, et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol 2007;22:2089-95. https://doi.org/10.1007/s00467-007-0601-4
  32. Lattanzio MR, Kopyt NP. Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment. J Am Osteopath Assoc 2009;109:13-9.
  33. Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P. Differential gene expression following early renal ischemia-reperfusion. Kidney Int 2003;63:1714-24. https://doi.org/10.1046/j.1523-1755.2003.00928.x
  34. Devarajan P, Mishra J, Supavekin S, Patterson LT, Potter SS. Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics. Mol Genet Metab 2003;80:365-76. https://doi.org/10.1016/j.ymgme.2003.09.012
  35. Han M, Li Y, Liu M, Li Y, Cong B. Renal neutrophil gelatinase associated lipocalin expression in lipopolysaccharide-induced acute kidney injury in the rat. BMC Nephrol 2012;13:25 https://doi.org/10.1186/1471-2369-13-25
  36. Hoffmann D, Fuchs TC, Henzler T, Matheis KA, Herget T, Dekant W, et al. Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity. Toxicology 2010;277:49-58. https://doi.org/10.1016/j.tox.2010.08.013
  37. Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005;115:610-21. https://doi.org/10.1172/JCI23056
  38. Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, et al. Plasma NGAL predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 2007;11:R127. https://doi.org/10.1186/cc6192
  39. Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol 2008;3:665-73. https://doi.org/10.2215/CJN.04010907
  40. Koyner JL, Garg AX, Coca SG, Sint K, Thiessen-Philbrook H, Patel UD, et al. Biomarkers predict progression of acute kidney injury after cardiac surgery. J Am Soc Nephrol 2012;23:905-14. https://doi.org/10.1681/ASN.2011090907
  41. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophilgelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol 2006;26:287-92. https://doi.org/10.1159/000093961
  42. Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A. 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 2009;54:1012-24. https://doi.org/10.1053/j.ajkd.2009.07.020
  43. Bagshaw SM, Bennett M, Haase M, Haase-Fielitz A, Egi M, Morimatsu H, et al. Plasma and urine neutrophil gelatinaseassociated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 2010;36:452-61. https://doi.org/10.1007/s00134-009-1724-9
  44. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31:703-11. https://doi.org/10.1093/eurheartj/ehp507
  45. Damman K, van Veldhuisen DJ, Navis G, Voors AA, HillegeHL. Urinary neutrophil gelatinase associated lipocalin (NGAL),a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 2008;10:997-1000. https://doi.org/10.1016/j.ejheart.2008.07.001
  46. Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, et al. The outcome of neutrophil gelatinaseassociated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011;57:1752-61. https://doi.org/10.1016/j.jacc.2010.11.051
  47. Viau A, El Karoui K, Laouari D, Burtin M, Nguyen C, Mori K, et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest 2010; 120:4065-76. https://doi.org/10.1172/JCI42004
  48. Kusaka M, Kuroyanagi Y, Mori T, Nagaoka K, Sasaki H, Maruyama T, et al. Serumneutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation applying donation after cardiac death. Cell Transplant 2008;17:129-34. https://doi.org/10.3727/000000008783907116
  49. Wasilewska A, Taranta-Janusz K, Debek W, Zoch-Zwierz W, Kuroczycka-Saniutycz E. KIM-1 and NGAL: new markers of obstructive nephropathy. Pediatr Nephrol 2011;26:579-86. https://doi.org/10.1007/s00467-011-1773-5
  50. Eddy AA, Neilson EG. Chronic kidney disease progression. J Am Soc Nephrol 2006;17:2964-6. https://doi.org/10.1681/ASN.2006070704
  51. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137-47. https://doi.org/10.7326/0003-4819-139-2-200307150-00013
  52. Clark WF, Macnab JJ, Sontrop JM, Jain AK, Moist L, Salvadori M, et al. Dipstick proteinuria as a screening strategy to identify rapid renal decline. J Am Soc Nephrol 2011;22:1729-36. https://doi.org/10.1681/ASN.2010111217
  53. Fassett RG, Venuthurupalli SK, Gobe GC, Coombes JS, Cooper MA, Hoy WE. Biomarkers in chronic kidney disease: a review. Kidney Int 2011;80:806-21. https://doi.org/10.1038/ki.2011.198
  54. Smith ER, Lee D, Cai MM, Tomlinson LA, Ford ML, McMahon LP, et al. Urinary neutrophil gelatinase-associated lipocalin may aidprediction of renal decline in patients with non-proteinuric Stages 3 and 4 chronic kidney disease (CKD). Nephrol Dial Transplant 2013;28:1569-79. https://doi.org/10.1093/ndt/gfs586
  55. Nickolas TL, Forster CS, Sise ME, Barasch N, Sola-Del Valle D, Viltard M, et al. NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease. Kidney Int 2012;82: 718-22. https://doi.org/10.1038/ki.2012.195
  56. Mitsnefes MM, Kathman TS, Mishra J, Kartal J, Khoury PR, Nickolas TL, et al. Serum neutrophil gelatinaseassociatedlipocalin as a marker of renal function in children with chronickidney disease. Pediatr Nephrol 2007;22:101-8. https://doi.org/10.1007/s00467-006-0244-x
  57. Bhavsar NA, Kottgen A, Coresh J, Astor BC. Neutrophil gelatinaseassociatedlipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 2012;60:233-40. https://doi.org/10.1053/j.ajkd.2012.02.336
  58. Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, et al. Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressivechronic kidney disease. Kidney Int 2013;83:909-14. https://doi.org/10.1038/ki.2012.458
  59. Braun V, Braun M. Active transport of iron and siderophore antibiotics. Curr Opin Microbiol. 2002;5:194-201. https://doi.org/10.1016/S1369-5274(02)00298-9
  60. Johnson JR, Lockman HA, Owens K, Jelacic S, Tarr PI. High-frequency secondary mutations after suicide-driven allelic exchange mutagenesis in extraintestinal pathogenic Escherichia coli. J Bacteriol 2003:185:5301-5. https://doi.org/10.1128/JB.185.17.5301-5305.2003
  61. Wu H, Santoni-Rugiu E, Ralfkiaer E, Porse BT, Moser C, Hoiby N, et al. Lipocalin 2 is protective against E. coli pneumonia. Respir Res 2010;11:96. https://doi.org/10.1186/1465-9921-11-96
  62. Ichino M, Kuroyanagi Y, KusakaM, Mori T, Ishikawa K, Shiroki R, et al. Increased urinary neutrophil gelatinase associated lipocalin levels in a rat model of upper urinary tract infection. J Urol 2009; 181:2326-31. https://doi.org/10.1016/j.juro.2009.01.010
  63. Wheeler DS, Devarajan P, Ma Q, Harmon K, Monaco M, Cvijanovich N, et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as amarker of acute kidney injury in critically ill children with septic shock. Crit Care Med 2008;36:1297-303. https://doi.org/10.1097/CCM.0b013e318169245a
  64. Xu S, Pauksen K, Venge P. Serum measurements of humanneutrophil lipocalin (HNL) discriminate between acute bacterial and viral infections. Scand J Clin Lab Invest 1995;55:125-31. https://doi.org/10.3109/00365519509089604
  65. Fjaertoft G, Foucard T, Xu S, Venge P. Human neutrophil lipocalin (HNL) as a diagnostic tool in children with acute infections: a study of the kinetics. Acta Paediatr 2005;94:661-6. https://doi.org/10.1111/j.1651-2227.2005.tb01961.x
  66. Bjorkqvist M, Kallman J, Fjaertoft G, Xu S, Venge P, Schollin J. Human neutrophil lipocalin: normal levels and use as a marker for invasive infection in the newborn. Acta Paediatr 2004;93:534-9. https://doi.org/10.1080/08035250410024754
  67. Montini G, Tullus K, Hewitt IK. Febrile urinary tract infections in children. N Engl J Med 2011; 365:239-50. https://doi.org/10.1056/NEJMra1007755
  68. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. 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 2011; 128:595-610. https://doi.org/10.1542/peds.2011-1330
  69. Rushton HG. The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. Pediatr Nephrol 1997;11:108-20. https://doi.org/10.1007/s004670050243

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