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Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function

2011; Elsevier BV; Volume: 79; Issue: 10 Linguagem: Inglês

10.1038/ki.2010.555

ISSN

1523-1755

Autores

Zoltán Endre, John W. Pickering, Robert Walker, Prasad Devarajan, Charles L. Edelstein, Joseph V. Bonventre, Christopher Frampton, Michael Bennett, Qing Ma, Venkata Sabbisetti, Vishal S. Vaidya, Angela Walcher, Geoffrey M. Shaw, Seton Henderson, Maryam Nejat, John Schollum, Peter M. George,

Tópico(s)

Chronic Kidney Disease and Diabetes

Resumo

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR 60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI. To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR 60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI. The unavoidable delay in the diagnosis of acute kidney injury (AKI) resulting from the use of plasma creatinine (PCr) has stimulated development of new urinary and plasma biomarkers.1.Han W.K. Bailly V. Abichandani R. et al.Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar, 2.Westhuyzen J. Endre Z.H. Reece G. et al.Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.Nephrol Dial Transplant. 2003; 18: 543-551Crossref PubMed Scopus (263) Google Scholar, 3.Parikh C.R. Abraham E. Ancukiewicz M. et al.Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (417) Google Scholar, 4.Han W.K. Wagener G. 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Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria.Intensive Care Med. 2007; 33: 409-413Crossref PubMed Scopus (287) Google Scholar, 10.Mehta R.L. Fluid balance and acute kidney injury: the missing link for predicting adverse outcomes?.Nat Clin Pract Nephrol. 2009; 5: 10-11Crossref PubMed Scopus (20) Google Scholar and further subject to the vagaries of determining baseline renal function in the large proportion of patients who present without a previous recorded PCr.11.Pickering J.W. Frampton C.M. Endre Z.H. Evaluation of trial outcomes in acute kidney injury by creatinine modeling.Clin J Am Soc Nephrol. 2009; 4: 1705-1715Crossref PubMed Scopus (33) Google Scholar, 12.Goldstein S.L. Devarajan P. Progression from acute kidney injury to chronic kidney disease: a pediatric perspective.Adv Chronic Kidney Dis. 2008; 15: 278-283Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 13.Bagshaw S.M. Uchino S. Cruz D. et al.A comparison of observed versus estimated baseline creatinine for determination of RIFLE class in patients with acute kidney injury.Nephrol Dial Transplant. 2009; 24: 2739-2751Crossref PubMed Scopus (163) Google Scholar, 14.Pickering J.W. Endre Z.H. Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive care unit.Clin J Am Soc Nephrol. 2010; 5: 1165-1173Crossref PubMed Scopus (108) Google Scholar Although discovery has been driven by the success of individual biomarkers in homogeneous populations, performance is poorer in more heterogeneous populations when time of renal injury is poorly defined.15.Siew E. Ware L. Gebretsadik T. et al.Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults.J Am Soc Nephrol. 2009; 20: 1823-1832Crossref PubMed Scopus (187) Google Scholar, 16.Endre Z.H. Walker R.J. Pickering J.W. et al.Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).Kidney Int. 2010; 77: 1020-1030Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar The same biomarkers perform differently under different conditions,17.Haase M. Bellomo R. Devarajan P. et al.Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.Am J Kid Dis. 2009; 54: 1012-1024Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar including differences in baseline glomerular filtration rate (GFR).18.McIlroy D. Wagener G. Lee H. 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: 211-219Crossref PubMed Scopus (157) Google Scholar The expectation that a panel of biomarkers could provide higher specificity and sensitivity for AKI in a heterogeneous population requires understanding of biomarker behavior under these conditions. In the largest biomarker study to date, we recently demonstrated that a urinary biomarker, the combination product of γ-glutamyltranspeptidase (GGT) and alkaline phosphatase (AP), facilitated randomization to intervention within 6.3±4.2 h (mean±s.d.) of entry to the intensive care unit (ICU) in the EARLYARF (Early Intervention in Acute Renal Failure) trial.16.Endre Z.H. Walker R.J. Pickering J.W. et al.Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).Kidney Int. 2010; 77: 1020-1030Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar Although the diagnosis of AKI was rapid compared with the usual 48–72 h delay based on creatinine-based methods, the transient increase in this biomarker combination compromised effective triaging to early intervention in this population with a heterogeneous duration of renal injury.16.Endre Z.H. Walker R.J. Pickering J.W. et al.Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).Kidney Int. 2010; 77: 1020-1030Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar Stratification for time after presumed injury improved biomarker performance.16.Endre Z.H. Walker R.J. Pickering J.W. et al.Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).Kidney Int. 2010; 77: 1020-1030Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar In the same study, we prospectively acquired urine and plasma for other novel biomarkers, including neutrophil-gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM)-1, and interleukin (IL)-18, each reported to have a high predictive value for AKI.19.Coca S.G. Yalavarthy R. Concato J. et al.Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review.Kidney Int. 2008; 73: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar We also analyzed urine and plasma for cystatin C (CysC) and reported these results separately.20.Nejat M. Pickering J.W. Walker R.J. et al.Rapid detection of acute kidney injury by plasma cystatin C in the intensive care unit.Nephrol Dial Transplant. 2010; 25: 3283-3289Crossref PubMed Scopus (132) Google Scholar, 21.Nejat M. Pickering J.W. Walker R.J. et al.Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and prognostic of mortality in the intensive care unit.Crit Care. 2010; 14: R85Crossref PubMed Scopus (102) Google Scholar We now report the first head-to-head comparison of these novel biomarkers in a heterogeneous high-risk population as diagnostic and predictive markers of AKI, need for dialysis, and prediction of mortality at 7 days in patients stratified both for time elapsed after renal insult and for GFR at time of ICU admission. Of 529 patients recruited, 1 withdrew all data leaving 528 patients for analysis. Patient characteristics and biomarker concentrations on entry are shown in Tables 1a and b.Table 1aPatient demographics (total cohort, n=528)Characteristics Age (years), mean±s.d.60±17 Female % (n)39.8 (210) Weight (kg), mean±s.d.80±19 APACHE II score, mean±s.d.18±6.4 SOFA score, mean±s.d.6.3±2.8Primary diagnosis (%) (n) Abdominal aortic aneurysm rupture and repair4.5 (24) Abdominal surgery or inflammation10.2 (54) Burns0.9 (5) Cardiac arrest or failure11.9 (63) Cardiac surgery17.8 (94) Collapse, cause unknown0.6 (3) Neurological surgery, injury, or seizure or hemorrhage14.0 (74) Other0.6 (3) Pulmonary or thoracic surgery or failure12.1 (64) Sepsis19.1 (101) Trauma8.1 (43)Outcomes (%) (n) AKIN on entry27.8 (147) AKIN4815.5 (82) RIFLE245.1 (27) Dialysis within 7 days3.6 (19) Died within 7 days10.2 (54)Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment.AKIN on entry: ≥0.3 mg/dl or ≥50% increase in plasma creatinine from baseline on entry to the ICU.AKIN48: Not AKIN on entry and ≥0.3 mg/dl or ≥50% increase in plasma creatinine from baseline within ∼48 h.RIFLE24: Not AKIN on entry and ≥50% increase in plasma creatinine sustained for ≥24 h within 7 days. Open table in a new tab Table 1bUrinary biomarker concentrations on entryNMean±s.d.Median (IQR)MinMaxGGT (Units/l)/mmol/l Cr52628±5513 (7–25)1.9923AP (Units/l)/mmol/l Cr5261.7±4.10.89 (0.46–1.8)0.0002574.8CysC (mg/l)/mmol/l Cr5220.40±1.10.016 (0.001–0.17)0.00019.3NGAL (ng/ml)/mmol/l Cr487140±4108.0 (2.5–41)0.00013000IL-18 (pg/ml)/mmol/l Cr52373±3400.001 (0.001–36)aSee distribution in Figure 1.0.00013100KIM-1 (pg/ml)/mmol/l Cr524300±140086 (37–210)0.562800Abbreviations: AP, alkaline phosphatase; Cr, creatinine; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; IQR, interquartile range; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin.a See distribution in Figure 1. Open table in a new tab Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment. AKIN on entry: ≥0.3 mg/dl or ≥50% increase in plasma creatinine from baseline on entry to the ICU. AKIN48: Not AKIN on entry and ≥0.3 mg/dl or ≥50% increase in plasma creatinine from baseline within ∼48 h. RIFLE24: Not AKIN on entry and ≥50% increase in plasma creatinine sustained for ≥24 h within 7 days. Abbreviations: AP, alkaline phosphatase; Cr, creatinine; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; IQR, interquartile range; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin. Urinary biomarker concentrations were moderately correlated with one another on entry to the ICU (Table 2), with the strongest correlations between the two brush border enzymes (GGT and AP, r=0.66) and between two freely filtered analytes (NGAL and CysC, r=0.60).Table 2Correlations among urinary biomarkers on entrySpearman’s rhoAP/uCrCysC/uCrNGAL/uCrIL-18/uCrKIM-1/uCrGGT/uCr0.660.240.330.330.25AP/uCr0.170.260.200.19CysC/uCr0.600.520.39NGAL/uCr0.410.41IL-18/uCr0.32Abbreviations: AP, alkaline phosphatase; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine.All correlations P<0.0001. Open table in a new tab Abbreviations: AP, alkaline phosphatase; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine. All correlations P 0.70). In patients without AKI on entry, AP, NGAL, and IL-18 were the strongest predictors of dialysis (Table 4). All biomarkers except KIM-1 were moderately predictive of death within 7 days (AUC >0.60, Table 3), especially IL-18 (AUC=0.68). GGT, CysC, NGAL, and IL-18 remained independently associated with mortality after adjusting for sex, age, weight, baseline estimated GFR (eGFR), Acute Physiology and Chronic Health Evaluation, and Sequential Organ Failure Assessment with odds ratios for a 10-fold increase in concentration of 2.37 (1.21–4.64), 1.53 (1.18–2.00), 1.66 (1.19–2.32), and 1.24 (1.08–1.42), respectively. Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine. No biomarker predicted AKI within 48 h (AKIN48) (Table 4). Only IL-18 predicted more severe AKI (RIFLE24: a≥50% increase in creatinine sustained for ≥24 hours within 7 days) with an AUC >0.7. Figure 1b highlights that even with this more severe definition of AKI, considerable scatter remained. After stratification by time after renal insult, all biomarkers except AP showed enhanced performance (Table 5). The results reflect both the time course of the individual biomarkers and the severity of insult. The effect of biomarker time course was further assessed by examining the predictive value for AKI within 48 h of entry (AKIN48, Table 5). The predictive value was greatest (AUC >0.7) for GGT 6–12 h after injury, and for CysC and IL-18 beyond 36 h after injury.Table 5AUCs for AKI stratified according to time after insultTime from insult<6 h (n=178 [37])6 to <12 h (n=94 [20])12 to <36 h (n=115 [48])≥36 h (n=107 [39])Diagnosis of AKI (AKI on entry)aAKI on entry: cohort: all patients on entry to the ICU (n=528). GGT/uCr0.70 (0.60–0.80)0.67 (0.52–0.81)0.61 (0.50–0.71)0.52 (0.40–0.63) AP/uCr0.60 (0.49–0.71)b<6h: significantly lower than the AUC for GGT/uCr.0.49 (0.34–0.63)c6 to <12h: significantly lower than the AUCs for GGT/uCr, CysC/uCr, and KIM-1/uCr.0.41 (0.30–0.51)d12 to <36h: significantly lower than the AUCs for all other biomarkers.0.39 (0.29–0.50)e≥36h: significantly lower than the AUCs for GGT/uCr, NGAL/uCr, and KIM-1/uCr. CysC/uCr0.67 (0.57–0.78)0.75 (0.62–0.88)0.68 (0.57–0.78)0.52 (0.41–0.64) NGAL/uCr0.66 (0.55–0.77)0.65 (0.50–0.80)0.71 (0.61–0.82)f≥36h: significantly higher than the AUCs for GGT/uCr and AP/uCr.0.60 (0.48–0.72) IL-18/uCr0.62 (0.52–0.73)0.67 (0.53–0.81)0.64 (0.53–0.74)0.51 (0.39–0.62) KIM-1/uCr0.62 (0.52–0.73)0.66 (0.52–0.81)0.67 (0.56–0.77)0.61 (0.49–0.72)Prediction of AKI (AKIN48)gAKIN48: all patients on entry to the ICU without AKI on entry (n=381).<6 h (n=141 [32])6 to <12 h (n=74 [15])12 to <36 h (n=67 [11])≥36 h (n=68 [18])GGT/uCr0.50 (0.39–0.62)0.71 (0.55–0.87)h6 to <12h: significantly higher than the AUC for NGAL/uCr.0.58 (0.39–0.77)0.47 (0.31–0.62)AP/uCr0.59 (0.48–0.71)0.63 (0.46–0.79)0.42 (0.25–0.60)0.47 (0.31–0.62)CysC/uCr0.48 (0.37–0.59)0.61 (0.45–0.78)0.48 (0.29–0.67)0.73 (0.59–0.88)i≥36h: significantly higher than the AUCs for all other biomarkers, except IL-18/uCr.NGAL/uCr0.53 (0.41–0.65)0.49 (0.31–0.67)0.55 (0.35–0.75)0.60 (0.44–0.77)j≥36h: significantly higher than the AUCs for all other biomarkers, except CysC/uCr.IL-18/uCr0.38 (0.28–0.49)k<6h: significantly lower than the AUCs for all other biomarkers, except CysC/uCr.0.60 (0.43–0.77)0.47 (0.28–0.65)0.75 (0.60–0.89)l≥36h: significantly higher than the AUCs for GGT/uCr.KIM-1/uCr0.54 (0.43–0.66)0.57 (0.40–0.74)0.47 (0.29–0.66)0.48 (0.32–0.64)Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine.The number in square brackets is the number of patients with AKI.a AKI on entry: cohort: all patients on entry to the ICU (n=528).b <6 h: significantly lower than the AUC for GGT/uCr.c 6 to <12 h: significantly lower than the AUCs for GGT/uCr, CysC/uCr, and KIM-1/uCr.d 12 to <36 h: significantly lower than the AUCs for all other biomarkers.e ≥36 h: significantly lower than the AUCs for GGT/uCr, NGAL/uCr, and KIM-1/uCr.f ≥36 h: significantly higher than the AUCs for GGT/uCr and AP/uCr.g AKIN48: all patients on entry to the ICU without AKI on entry (n=381).h 6 to <12 h: significantly higher than the AUC for NGAL/uCr.i ≥36 h: significantly higher than the AUCs for all other biomarkers, except IL-18/uCr.j ≥36 h: significantly higher than the AUCs for all other biomarkers, except CysC/uCr.k <6 h: significantly lower than the AUCs for all other biomarkers, except CysC/uCr.l ≥36 h: significantly higher than the AUCs for GGT/uCr. Open table in a new tab Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine. The number in square brackets is the number of patients with AKI. When biomarker concentration was stratified by baseline eGFR, there was a marginal improvement in the diagnostic performance with CysC and KIM-1 having AUC ≥0.7 in the subcohort with eGFR 0.7 in the subcohort with eGFR 90–120 ml/min (Table 6). Predictive performance remained poor, except where eGFR <60 ml/min; here, GGT had the highest AUC (0.79).Table 6AUCs for AKI stratified according to eGFReGFR<60 ml/min (n=96 [27])60 to <90 ml/min (n=172 [56])90 to <120 ml/min (n=162 [34])≥120 ml/min (n=96 [30])Diagnosis of AKI (AKI on entry)aAKI on entry: cohort: all patients on entry to the ICU (n=528). GGT/uCr0.46 (0.33–0.59)0.60 (0.50–0.69)0.66 (0.55–0.76)0.62 (0.49–0.74) AP/uCr0.37 (0.25–0.49)0.46 (0.37–0.55)b60 to <90ml/min and 90 to <120ml/min: significantly lower than the AUCs for all other biomarkers.0.45 (0.35–0.56)b60 to <90ml/min and 90 to <120ml/min: significantly lower than the AUCs for all other biomarkers.0.51 (0.38–0.63)c≥120ml/min: significantly lower than the AUCs for GGT/uCr, CysC/uCr, and NGAL/uCr. CysC/uCr0.72 (0.60–0.84)d<60ml/min: significantly higher than the AUCs for GGT/uCr and AP/uCr.0.60 (0.51–0.70)0.75 (0.65–0.85)e90 to <120ml/min: significantly higher than the AUCs for AP/uCr and KIM-1/uCr.0.66 (0.54–0.79) NGAL/uCr0.64 (0.50–0.78)d<60ml/min: significantly higher than the AUCs for GGT/uCr and AP/uCr.0.64 (0.54–0.73)0.70 (0.59–0.81)0.69 (0.56–0.81)f≥120ml/min: significantly higher than the AUCs for AP/uCr and IL-18/uCr. IL-18/uCr0.65 (0.52–0.77)d<60ml/min: significantly higher than the AUCs for GGT/uCr and AP/uCr.0.60 (0.51–0.69)0.67 (0.56–0.78)0.56 (0.43–0.68) KIM-1/uCr0.70 (0.58–0.82)d<60ml/min: significantly higher than the AUCs for GGT/uCr and AP/uCr.0.68 (0.59–0.77)0.63 (0.52–0.74)0.61 (0.49–0.74)Prediction of AKI (AKIN48)gAKIN48: cohort: all patients on entry to the ICU without AKI on entry (n=381).<60 ml/min (n=69 [20])60 to <90 ml/min (n=116 [25])90 to <120 ml/min (n=128 [26])≥120 ml/min (n=66 [11])GGT/uCr0.79 (0.66–0.92)0.48 (0.35–0.60)0.50 (0.37–0.62)0.56 (0.36–0.75)h≥120ml/min: significantly higher than the AUCs for CysC/uCr and KIM-1/uCr.AP/uCr0.71 (0.56–0.85)0.48 (0.35–0.60)0.54 (0.41–0.66)0.55 (0.36–0.74)CysC/uCr0.64 (0.49–0.79)0.54 (0.41–0.67)0.58 (0.45–0.71)0.35 (0.18–0.51)NGAL/uCr0.71 (0.56–0.87)0.53 (0.39–0.67)0.53 (0.41–0.66)0.44 (0.25–0.63)IL-18/uCr0.65 (0.50–0.80)0.48 (0.35–0.60)0.57 (0.45–0.70)0.49 (0.30–0.67)KIM-1/uCr0.66 (0.52–0.81)0.44 (0.32–0.56)0.65 (0.52–0.77)0.37 (0.20–0.54)Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; eGFR, estimated glomerular filtration rate; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine.The number in square brackets is the number of patients with AKI.a AKI on entry: cohort: all patients on entry to the ICU (n=528).b 60 to <90 ml/min and 90 to <120 ml/min: significantly lower than the AUCs for all other biomarkers.c ≥120 ml/min: significantly lower than the AUCs for GGT/uCr, CysC/uCr, and NGAL/uCr.d <60 ml/min: significantly higher than the AUCs for GGT/uCr and AP/uCr.e 90 to <120 ml/min: significantly higher than the AUCs for AP/uCr and KIM-1/uCr.f ≥120 ml/min: significantly higher than the AUCs for AP/uCr and IL-18/uCr.g AKIN48: cohort: all patients on entry to the ICU without AKI on entry (n=381).h ≥120 ml/min: significantly higher than the AUCs for CysC/uCr and KIM-1/uCr. Open table in a new tab Abbreviations: AKI, acute kidney injury; AKIN48, AKI within 48 h; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; eGFR, estimated glomerular filtration rate; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine. The number in square brackets is the number of patients with AKI. Stratifying biomarker concentration according to time after renal insult may explain the time dependence of some biomarker performance (Figure 2). A decline in GGT and AP concentrations with time suggests that these pre-formed brush border enzymes are excreted in diminishing amounts after injury. The remaining biomarkers demonstrated increasing concentrations with time in AKI patients consistent with induction, although at different rates. IL-18, CysC, and KIM-1 exhibited a brief increase, whereas the increase in NGAL was more sustained. CysC continued to increase, whereas IL-18 and NGAL had a possible biphasic pattern which may be explained by ongoing injury especially in patients with sepsis; these entered the ICU later after insult than did other patients (29 (interquartile range 16–82) h for sepsis versus 6.2 (4.2–18) h, P<0.0001). The effect of stratifying biomarker concentration according to both time after renal insult and baseline eGFR is summarized in the contour plots of AUC for AKI on entry for each biomarker in Figure 3. Individual values are shown for stratification into only two groups (<60 and ≥60 ml/min) in Table 7 and for all eGFR groups in Appendix Table 1.Table 7AUCs for diagnosis of AKI according to time after insult and eGFR<6 h6 to <12 h12 to <36 h≥36 heGFR (ml/min)Time from insultn=24 [3]n=40 [4]n=12 [8]n=20 [12]<60GGT/uCr0.41 (0.08–0.75)0.26 (0.04–0.49)0.91 (0.73–1)0.48 (0.21–0.74)AP/uCr0.17 (0–0.38)0.19 (0.01–0.37)0.62 (0.29–0.96)0.40 (0.13–0.66)CysC/uCr0.69 (0.34–1)0.65 (0.35–0.96)0.88 (0.67–1)0.44 (0.17–0.70)NGAL/uCr0.45 (0.10–0.80)0.39 (0.07–0.7)0.85 (0.58–1)0.58 (0.32–0.84)IL-18/uCr0.62 (0.26–0.98)0.61 (0.30–0.92)0.94 (0.80–1)0.41 (0.14–0.67)KIM-1/uCr0.73 (0.39–1)0.43 (0.14–0.72)0.66 (0.33–0.98)0.65 (0.40–0.89)n=153 [34]n=83 [17]n=104 [41]n=90 [28]≥60GGT/uCr0.73 (0.62–0.83)0.78 (0.64–0.92)0.57 (0.45–0.68)0.55 (0.42–0.68)AP/uCr0.64 (0.53–0.75)0.62 (0.46–0.77)0.37 (0.26–0.48)0.4 (0.28–0.52)CysC/uCr0.68 (0.57–0.79)0.77 (0.63–0.91)0.65 (0.54–0.76)0.53 (0.40–0.66)NGAL/uCr0.68 (0.57–0.80)0.69 (0.52–0.85)0.71 (0.60–0.82)0.57 (0.43–0.71)IL-18/uCr0.63 (0.51–0.74)0.72 (0.57–0.87)0.58 (0.47–0.70)0.54 (0.41–0.68)KIM-1/uCr0.62 (0.51–0.73)0.72 (0.57–0.87)0.66 (0.55–0.77)0.58 (0.45–0.71)Abbreviations: AKI, acute kidney injury; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; eGFR, estimated glomerular filtration rate; GGT, γ-glutamyltranspeptidase; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine.n=total number in category. Square brackets show number of patients with AKI. Open table in a new tab Table A1AUC for diagnosis of AKI according to time after insult and eGFR<6 h6 to <12 h12 to <36 h≥36 heGFR (ml/min)Time from insultn=24 [3]n=40 [4]n=12 [8]n=20 [12]<60GGT/uCr0.41 (0.08–0.75)0.26 (0.04–0.49)0.91 (0.73–1)0.48 (0.21–0.74)AP/uCr0.17 (0–0.38)0.19 (0.01–0.37)0.62 (0.29–0.96)0.40 (0.13–0.66)CysC/uCr0.69 (0.34–1)0.65 (0.35–0.96)0.88 (0.67–1)0.44 (0.17–0.70)NGAL/uCr0.45 (0.10–0.80)0.39 (0.07–0.7)0.85 (0.58–1)0.58 (0.32–0.84)IL-18/uCr0.62 (0.26–0.98)0.61 (0.30–0.92)0.94 (0.80–1)0.41 (0.14–0.67)KIM-1/uCr0.73 (0.39–1)0.43 (0.14–0.72)0.66 (0.33–0.98)0.65 (0.40–0.89)n=64 [14]n=27 [9]n=43 [16]n=38 [17]60–<90GGT/uCr0.70 (0.53–0.86)0.69 (0.46–0.91)0.67 (0.50–0.84)0.48 (0.30–0.67)AP/uCr0.65 (0.47–0.82)0.55 (0.31–0.79)0.38 (0.21–0.55)0.41 (0.23–0.59)CysC/uCr0.63 (0.46–0.81)0.65 (0.42–0.88)0.59 (0.41–0.77)0.40 (0.22–0.58)NGAL/uCr0.58 (0.40–0.76)0.60 (0.35–0.85)0.72 (0.54–0.89)0.52 (0.33–0.72)IL-18/uCr0.61 (0.44–0.79)0.73 (0.52–0.95)0.58 (0.40–0.76)0.43 (0.24–0.61)KIM-1/uCr0.75 (0.59–0.91)0.66 (0.43–0.89)0.72 (0.56–0.89)0.44 (0.26–0.63)n=56 [10]n=35 [5]n=35 [14]n=32 [5]90–<120GGT/uCr0.87 (0.73–1)0.85 (0.64–1)0.

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