title: The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies.
abstract: OBJECTIVE
  The aim of this study was to test the hypothesis that, without diagnostic changes in serum creatinine, increased neutrophil gelatinase-associated lipocalin (NGAL) levels identify patients with subclinical acute kidney injury (AKI) and therefore worse prognosis.
  
  
  BACKGROUND
  Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function.
  
  
  METHODS
  We analyzed pooled data from 2,322 critically ill patients with predominantly cardiorenal syndrome from 10 prospective observational studies of NGAL. We used the terms NGAL(-) or NGAL(+) according to study-specific NGAL cutoff for optimal AKI prediction and the terms sCREA(-) or sCREA(+) according to consensus diagnostic increases in serum creatinine defining AKI. A priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in intensive care and in-hospital.
  
  
  RESULTS
  Of study patients, 1,296 (55.8%) were NGAL(-)/sCREA(-), 445 (19.2%) were NGAL(+)/sCREA(-), 107 (4.6%) were NGAL(-)/sCREA(+), and 474 (20.4%) were NGAL(+)/sCREA(+). According to the 4 study groups, there was a stepwise increase in subsequent renal replacement therapy initiation-NGAL(-)/sCREA(-): 0.0015% versus NGAL(+)/sCREA(-): 2.5% (odds ratio: 16.4, 95% confidence interval: 3.6 to 76.9, p < 0.001), NGAL(-)/sCREA(+): 7.5%, and NGAL(+)/sCREA(+): 8.0%, respectively, hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (4-group comparisons: all p < 0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(-)/sCREA(-): 4.2 and 8.8 days; NGAL(+)/sCREA(-): 7.1 and 17.0 days; NGAL(-)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; 4-group comparisons: p = 0.003 and p = 0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern.
  
  
  CONCLUSIONS
  In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI might need re-assessment.
authors.affiliation: Department of Nephrology and Intensive Care, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haase
authors.forename: Prasad
authors.initials: P
authors.lastname: Devarajan
authors.forename: Anja
authors.initials: A
authors.lastname: Haase-Fielitz
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.forename: Dinna N
authors.initials: DN
authors.lastname: Cruz
authors.forename: Gebhard
authors.initials: G
authors.lastname: Wagener
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Krawczeski
authors.forename: Jay L
authors.initials: JL
authors.lastname: Koyner
authors.forename: Patrick
authors.initials: P
authors.lastname: Murray
authors.forename: Michael
authors.initials: M
authors.lastname: Zappitelli
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Goldstein
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Makris
authors.forename: Claudio
authors.initials: C
authors.lastname: Ronco
authors.forename: Johan
authors.initials: J
authors.lastname: Martensson
authors.forename: Claes-Roland
authors.initials: CR
authors.lastname: Martling
authors.forename: Per
authors.initials: P
authors.lastname: Venge
authors.forename: Edward
authors.initials: E
authors.lastname: Siew
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: T Alp
authors.initials: TA
authors.lastname: Ikizler
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000175:diagnosis* / Q000652:urine; D000209:Acute-Phase Proteins / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood* / Q000652:urine*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000097:blood* / Q000652:urine*; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins