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Cardiovascular & Hematological Disorders-Drug Targets


ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Research Article

Neutrophil Gelatinase-associated Lipocalin as a Marker of Postoperative Acute Kidney Injury Following Cardiac Surgery in Patients with Preoperative Kidney Impairment

Author(s): N. Tidbury, N. Browning, M. Shaw, M. Morgan , I. Kemp and B. Matata*

Volume 19, Issue 3, 2019

Page: [239 - 248] Pages: 10

DOI: 10.2174/1871529X19666190415115106

Price: $65


Introduction: Acute kidney injury (AKI) is a serious complication of cardiac surgery. The current ‘gold standard’ for determining AKI is change in serum creatinine and urine output, however, this change occurs relatively late after the actual injury occurs. Identification of new biomarkers that detect early AKI is required. Recently, new biomarkers, such as the NephroCheck® Test and AKIRisk have also been tested and found to be good indicators of AKI. Neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in paediatric patients but has displayed varied results in adult populations, particularly post cardiac surgery. The aim of this study was to assess the value of urinary NGAL as a biomarker of AKI in patients with pre-existing renal impairment (eGFR >15ml/min to eGFR<60ml/min).

Methods: A post-hoc analysis of urinary NGAL concentrations from 125 patients with pre-existing kidney impairment, who participated in a randomised trial of haemofiltration during cardiac surgery, was undertaken. Urinary NGAL was measured using ELISA at baseline, post-operatively and 24 and 48 hours after surgery, and serum creatinine was measured pre and postoperatively and then at 24, 48, 72 and 96 hours as routine patient care. NGAL concentrations were compared in patients with and without AKI determined by changes in serum creatinine concentrations. A Kaplan-Meier plot compared survival for patients with or without AKI and a Cox proportional hazards analysis was performed to identify factors with the greatest influence on survival.

Results: Following surgery, 43% of patients developed AKI (based on KDIGO definition). Baseline urinary NGAL was not found to be significantly different between patients that did and did not develop AKI. Urinary NGAL concentration was increased in all patients following surgery, regardless of whether they developed AKI and was also significant between groups at 24 (p=0.003) and 48 hours (p<0.0001). Urinary NGAL concentrations at 48 hours correlated with serum creatinine concentrations at 48 hours (r=0.477, p<0.0001), 72 hours (r=0.488, p<0.0001) and 96 hours (r=0.463, p<0.0001). Urinary NGAL at 48 hours after surgery strongly predicted AKI (AUC=0.76; P=0.0001). A Kaplan- Meier plot showed that patients with postoperative AKI had a significantly lower 7-year survival compared with those without AKI. Postoperative urinary NGAL at 48 hours >156ng/mL also strongly predicted 7-year survival. However, additive EuroSCORE, age, current smoking and post-operative antibiotics usage were distinctly significantly more predictive of 7-year survival as compared with postoperative urinary NGAL at 48 hours >156ng/mL.

Conclusions: Our study demonstrated that postoperative urinary NGAL levels at 48 hours postsurgery strongly predicts the onset or severity of postoperative AKI based on KDIGO classification in patients with preoperative kidney impairment and were also strongly related to 7-year survival.

Keywords: Acute kidney injury, NGAL, cardiac surgery, renal impairment, lipocalin, ELISA.

Graphical Abstract
Uchino, S.; Kellum, J.A.; Bellomo, R.; Doig, G.S. Morimatsu, H.; Morgera, S.; Schetz, M.; Tan, I.; Bouman, C.; Macedo, E.; Gibney, N.; Tolwani, A.; Ronco, C.; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA, 2005, 294(7), 813-818.
Mao, H.; Katz, N.; Ariyanon, W.; Blanca-Martos, L.; Adýbelli, Z.; Giuliani, A.; Danesi, T.H.; Kim, J.C.; Nayak, A.; Neri, M.; Virzi, G.M.; Brocca, A.; Scalzotto, E.; Salvador, L.; Ronco, C. Cardiac surgery-associated acute kidney injury. Cardiorenal Med., 2013, 3(3), 178-199.
Hansen, M.K.; Gammelager, H.; Mikkelsen, M.M.; Hjortdal, V.E.; Layton, J.B.; Johnsen, S.P.; Christiansen, C.F. Post-operative acute kidney injury and five-year risk of death, myocardial infarction, and stroke among elective cardiac surgical patients: A cohort study. Crit. Care, 2013, 17(6), R292.
Rosner, M.H.; Okusa, M.D. Acute kidney injury associated with cardiac surgery. Clin. J. Am. Soc. Nephrol., 2006, 1(1), 19-32.
Thiele, R.H.; Isbell, J.M.; Rosner, M.H. AKI associated with cardiac surgery. Clin. J. Am. Soc. Nephrol., 2015, 10, 500-514.
Kiers, H.D.; van den Boogaard, M.; Schoenmakers, M.C.J.; van der Hoeven, J.G.; van Swieten, H.A.; Heemskerk, S.; Pickkers, P. Comparison and clinical suitability of eight prediction models for cardiac surgery-related acute kidney injury. Nephrol. Dial. Transplant., 2013, 28, 345-351.
Garg, A.X.; Shehata, N.; McGuinness, S.; Whitlock, R.; Fergusson, D.; Wald, R.; Parikh, C.; Bagshaw, S.M.; Khanykin, B.; Gregory, A.; Syed, S.; Hare, G.M.T.; Cuerden, M.S.; Thorpe, K.E.; Hall, J.; Verma, S.; Roshanov, P.S.; Sontrop, J.M.; Mazer, C.D. (2018) Risk of acute kidney injury in patients randomized to a restrictive versus liberal approach to red blood cell transfusion in cardiac surgery: A substudy protocol of the transfusion requirements in cardiac surgery III noninferiority trial. Can. J. Kidney Health Dis., 2018, (5) 2054358117749532
Dasta, J.F.; Kane-Gill, S.L.; Durtschi, A.J.; Pathak, D.S.; Kellum, J.A. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol. Dial. Transplant., 2008, 23, 1970-1974.
Chertow, G.M.; Burdick, E.; Honour, M.; Bonventre, J.V.; Bates, D. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol., 2005, 16, 3365-3370.
Ishani, A.; Nelson, D.; Clothier, B.; Schult, T.; Nugent, S.; Greer, N.; Slinin, Y.; Ensrud, K.E. The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch. Intern. Med., 2011, 171, 226-233.
Machado, M.N.; Nakazone, M.A.; Maia, L.N. Acute kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery. Rev. Bras. Cir. Cardiovasc., 2014, 29(3), 299-307.
Nickolas, T.L.; Forster, C.S.; Sise, M.E.; Barasch, N.; Valle, D.S. -; Viltard, M.; Buchen, C.; Kupferman, S.; Carnevali, M.L.; Bennett, M.; Mattei, S.; Bovino, A.; Argentiero, L.; Magnano, A.; Devarajan, P.; Mori, K.; Erdjument-Bromage, H.; Tempst, P.; Allegri, L.; Barasch, J. NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease. Kidney Int., 2012, 82(6), 718-722.
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(1), 25.
Dent, C.L.; Ma, Q.; Dastrala, S.; Bennett, M.; Mitsnefes, M.M.; Barasch, J.; Devarajan, P. 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), R:127.
Mishra, J.; Dent, C.; Tarabishi, R.; Mitsnefes, M.M.; Ma, Q.; Kelly, C.; Ruff, S.M.; Zahedi, K.; Shao, M.; Bean, J.; Mori, K.; Barasch, J. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet, 2005, 365(9466), 1231-1238.
Friedrich, M.G.; Bougioukas, I.; Kolle, J.; Bireta, C.; Jebran, F.A.; Placzek, M.; Tirilomis, T.N. GAL expression during cardiopulmonary bypass does not predict severity of postoperative acute kidney injury. BMC Nephrol., 2017, 18(1), 1-7.
Koyner, J.L.; Bennett, M.R.; Worcester, E.M.; Ma, Q.; Raman, J.; Jeevanandam, V.; Kasza, K.E.; O’Connor, M.F.; Konczal, D.J.; Trevino, S.; Devarajan, P.; Murray, P.T. l Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery. Kidney Int., 74(8) 2008, , 1059-1069.
Wagener, G.; Jan, M.; Kim, M.; Mori, K.; Barasch, J.M.; Sladen, R.N.; Lee, H.T. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology, 2006, 105(3), 485-491.
Wagener, G.; Gubitosa, G.; Wang, S.; Borregaard, N.; Kim, M.; Lee, H.T. Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery. Am. J. Kidney Dis., 2008, 52(3), 425-433.
McMahon, G.M.; Waikar, S.S. Biomarkers in nephrology: Core Curriculum 2013. Am. J. Kidney Dis., 2013, 62, 165-178.
Devarajan, P. Neutrophil gelatinase-associated lipocalin: Apromising biomarker for human acute kidney injury. Biomarkers Med., 2010, 4, 265-280.
Matata, B.M.; Scawn, N.; Morgan, M.; Shirley, S.; Kemp, I.; Richards, S.; Lane, S.; Wilson, K.; Stables, R.; Jackson, M.; Haycox, A.; Mediratta, N. A single-center randomized trial of intraoperative zero-balanced ultrafiltration during cardiopulmonary bypass for patients with impaired kidney function undergoing cardiac surgery. J. Cardiothorac. Vasc. Anesth., 2015, 29(5), 1236-1247.
KDIGO Clinical Practice Guideline for Acute Kidney Injury Kidney International Supplements. 2012, 2, 1.
[ 2012.1]
Wright, G. Hemolysis during cardiopulmonary bypass: Update. Perfusion, 2001, 16, 345-351.
Baliga, R.; Ueda, N.; Waler, P.D.; Shah, S.V. Oxidant mechanisms in toxic acute renal failure. Am. J. Kidney Dis., 1997, 29, 465-477.
Davis, C.L.; Kausz, A.T.; Zager, R.A.; Kharasch, E.D.; Cochran, R.P. Acute renal failure after cardiopulmonary bypass is related to decreased serum ferritin levels. J. Am. Soc. Nephrol., 1999, 10, 2396-2402.
Messmer, K. Hemodilution. Surg. Clin. North Am., 1975, 55, 659-678.
Shah, D.; Corson, J.; Karmody, A.; Leather, R. Effects of isovolemichemodilution on abdominal aortic aneurysmectomy in high risk patients. Ann. Vasc. Surg., 1986, 1, 50-54.
Swaminathan, M.; Phillips-Bute, B.G.; Conlon, P.J.; Smith, P.K.; Newman, M.F.; Stafford-Smith, M. The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery. Ann. Thorac. Surg., 2003, 76, 784-792.
Karkouti, K.; Beattie, W.S.; Wijeysundera, D.N.; Rao, V.; Chan, C.; Dattilo, K.M.; Djaiani, G.; Ivanov, J.; Karski, J.; David, T.E. Hemodilution during cardiopulmonary bypass is an independent risk factor for acute renal failure in adult cardiac surgery. J. Thorac. Cardiovasc. Surg., 2005, 129, 391-400.
Kjeldsen, L.; Johnsen, A.H.; Sengelov, H.; Borregaard, N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J. Biol. Chem., 1993, 268(14), 10425-10432.
Schmidt-Ott, K.M.; Mori, K.; Jau, Y.L.; Kalandadze, A.; Cohen, D.J.; Devarajan, P.; Barasch, J. Dual action of neutrophil gelatinase-associated lipocalin. J. Am. Soc. Nephrol., 2007, 18(2), 407-413.
Goetz, D.H.; Holmes, M.A.; Borregaard, N.; Bluhm, M.E.; Raymond, K.N.; Strong, R.K. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell, 2002, 10(5), 1033-1043.
Mishra, J.; Qing, M.A.; Prada, A.; Mitsnefes, M.; Zahedi, K.; Yang, J.; Barasch, J.; Devarajan, P. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J. Am. Soc. Nephrol., 2003, 14(10), 2534-2543.
Mori, K.; Lee, H.T.; Rapoport, D.; Drexler, I.R.; Foster, K.; Yang, J.; Schmidt-Ott, K.M.; Chen, X.; Li, J.Y.; Weiss, S.; Mishra, J.; Cheema, F.H.; Markowitz, G.; Suganami, T.; Sawai, K.; Mukoyama, M.; Kunis, C.; D’Agati, V.; Devarajan, P.; Barasch, J. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J. Clin. Invest., 2005, 115(3), 610-621.
Hemdahl, A.; Gabrielsen, A.; Zhu, C.; Eriksson, P.; Hedin, U.; Kastrup, J. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler. Thromb. Vasc. Biol., 2006, 26(1), 136-142.
Eilenberg, W.; Stojkovic, S.; Piechota-Polanczyk, A. Kaun, C.; Rauscher, S.; Gröger, M.; Klinger, M.; Wojta, J.; Neumayer, C.; Huk, I.; Demyanets, S. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is associated with symptomatic carotid atherosclerosis and drives pro-inflammatory state in vitro. Eur. J. Vasc. Endovasc. Surg., 2016, 51(5), 623-631.
Kashani, K.; Al-Khafaji, A.; Ardiles, T.; Artigas, A.; Bagshaw, S.M.; Bell, M.; Bihorac, A.; Birkhahn, R.; Cely, C.M.; Chawla, L.S.; Davison, D.L.; Feldkamp, T.; Forni, L.G.; Gong, M.N.; Gunnerson, K.J.; Haase, M.; Hackett, J.; Honore, P.M.; Hoste, E.A.; Joannes-Boyau, O.; Joannidis, M.; Kim, P.; Koyner, J.L.; Laskowitz, D.T.; Lissauer, M.E.; Marx, G.; McCullough, P.A.; Mullaney, S.; Ostermann, M.; Rimmelé, T.; Shapiro, N.I.; Shaw, A.D.; Shi, J.; Sprague, A.M.; Vincent, J.L.; Vinsonneau, C.; Wagner, L.; Walker, M.G.; Wilkerson, R.G.; Zacharowski, K.; Kellum, J.A. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit. Care, 2013, 17, R25.
McCullough, P.A.; Shaw, A.D.; Haase, M.; Bouchard, J.; Waikar, S.S.; Siew, E.D.; Murray, P.T.; Mehta, R.L.; Ronco, C. Diagnosis of acute kidney injury using functional and injury biomarkers: Workgroup statements from the tenth acute dialysis quality initiative consensus conference. Contrib. Nephrol., 2013, 182, 13-29.
Boonstra, J.; Post, J.A. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene, 2004, 337, 1-13.
Seo, D.W.; Li, H.; Qu, C.K.; Oh, J.; Kim, Y.S.; Diaz, T.; Wei, B.; Han, J.W.; Stetler-Stevenson, W.G. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J. Biol. Chem., 2006, 281, 3711-3721.
Price, P.N.; Safirstein, R.L.; Megyesi, J. The cell cycle and acute kidney injury. Kidney Int., 2009, 76, 604-613.

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