Table 1.

Summary of the Recent Prospective AKI Biomarker Studies

Authors and year	Clinical Settings	Sample Size	Biomarkers	Endpoint	Summary of Findings
Parikh et al, 2011[30, 31**]	Undergoing cardiac surgery	1219 adults 311 pediatric	pNGAL, uNGAL, uIL-18	AKI prediction In-hospital and ICU LOS, RRT, mortality	Adult: AUCs for severe AKI diagnosis uNGAL 0.67, pNGAL 0.70, uIL-18 0.74. After multivariate adjustment, highest quintiles of postoperative levels of pNGAL and uIL-18 had between a 5- to 7-fold incremental risk of severe AKI, uNGALnot significant.
					Pediatric: AUCs for severe AKI diagnosis uNGAL 0.71, pNGAL 0.56, uIL-18 0.72. After multivariate adjustment, the highest quintiles of uNGAL and uIL-18 levels 4- 7-fold incremental risk for AKI relative to the lowest quintiles, pNGAL not sign.
					22 to 25% improvement in net reclassification index for uIL-18 in both studies, a 14 to 17% improvement for plasma and urine NGAL in the pediatric study, and an 18% improvement for pNGAL in the adult study.
					All biomarkers showed a significant ability to predict harder clinical endpoints including survival and duration of care (ventilation, ICU, and hospital days).
Haase et al, 2011[32**]	Cardiac Surgery + ICU (pooled cohorts)	2322 adults (10 studies)	NGAL	RRT, Mortality, LOS	NGAL-/Cr- (55.8%), NGAL+/Cr- (19.2%), NGAL-/Cr+ (4.6%), NGAL+/Cr+ (20.4%). Graded stepwise increase in risk for RRT, mortality, and length of stay. NGAL provides prognostic information beyond creatinine alone.
Krawczeski et al, 2011[33]	Cardiac surgery	220 pediatric	uNGAL, uKIM-1, uL-FABP,uIL-18	Timing of biomarker elevation and AKI prediction (50% increase in SCr)	Earliest significant elevation after CPB (NGAL 2 hrs., IL-18 and L-FABP 6 hrs., and KIM-1 12 hrs.). AUC for AKI at 2 hrs. clinical model 0.74, + uNGAL 0.85. At 6 hrs., clinical model 0.72, + uNGAL 0.91, + uIL-18 0.84, + L-FABP 0.77. At 12 hrs. clinical model 0.72,+ KIM-1 0.79. Net reclassification and integrated discrimination improved for each biomarker at varying time points.
Endre et al, 2011[34]	ICU	528 adults	uGGT, uAP, uNGAL uCystatin-C,uKIM-1 uIL-18	Diagnosis of AKI on entry, early diagnosis of AKI, RRT, Mortality	AUC for AKI on entry or prediction (all < 0.7). AUC for prediction of RRT (7 days) for NGAL, Cystatin C, IL-18 b/w 0.7-0.8. AUCS for prediction of death (7 days) all < 0.7. Prediction of AKI seemed to improve in the subset of those with abnormal eGFR < 60 ml/min/1.73m2 and varied with time from presumed insult.
Krawczeski et al, 2011[35]	Cardiac surgery	374 neonates and children	pNGAL, uNGAL	Early AKI Diagnosis, severity of AKI, Hospital LOS	Ability of early post-operative uNGAL and pNGAL to predict AKI in 48 hours (0.3 mg/dl increase creatinine in neonates, 50% increase in non-neonates). AUC from 2-48 hours following CPB ranged from 0.88-0.97 though most robust at 2-hour time point. In non-neonates, strong correlation observed between 2-hour NGAL levels and length of stay, and severity/duration of AKI.
De Geus et al, 2011[36]	ICU	632 adults	pNGAL, uNGAL	Early Diagnosis of AKI	AUC for early diagnosis of AKI using RIFLE R (pNGAL 0.77 ± 0.05, uNGAL 0.80 ± 0.04). Performance improved with increasing AKI severity. Biomarker levels improved discrimination, calibration, and net reclassification of a clinical model for severe AKI (RIFLE F).
Doi et al, 2011[37]	Medical-surgical mixed ICU	339 adults	uL-FABP, NGAL, IL-18, N-acetyl β-DG, Albumin	Early Diagnosis of AKI (50% increase in SCr), Mortality	AUC for early diagnosis of AKI (uL-FABP 0.75, uNGAL 0.70, uIL-18 0.69, uNAG 0.62, urinary albumin 0.69). AUC for prediction of 14 day mortality uL-FABP 0.90, uNGAL 0.83, uIL-18 0.83, uL-FABP + uNGAL = 0.93).
Shlipak et al, 2011[38]	Undergoing cardiac surgery (TRIBE-AKI)	1147 adults	Serum Cystatin-C	Presurgical Risk Stratification for AKI	Presurgical cystatin c performed better than creatinine/eGFR for estimating risk of AKI. Adjusted ORs for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4-2.7) and 4.8 (95% CI, 2.9-7.7) compared with 1.2 (95% CI, 0.9-1.7) and 1.8 (95% CI, 1.2-2.6) for creatinine. After adjustment for clinical predictors, AUC for AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C improved AKI risk classification compared with creatinine, based on a net reclassification index of 0.21 (P < 0.001).
Srisawat et al 2011[39]	Hospitalized with pneumonia	181 adults	pNGAL	Prediction of recovery from RIFE- Failure during hospitalization)	pNGAL alone predicted failure to recovery with AUC 0.74. Clinical model + NGAL did not improve AUC, but did improve net reclassification index by 17%.
Perry et al, 2010[40]	Undergoing cardiac surgery	879 adults	pNGAL	Early Diagnosis of AKI (50% increase in SCr)	pNGAL values did not reliably predict subsequent AKI (AUC immediately post-CPB 0.64, POD#1 0.67) though did associate independently after multivariate adjustment (for levels 353.5 ng/ml)(odds ratio, 2.3; 95% CI: 1.5–6.5)
Siew et al, 2010[41]	Mixed ICU population	451 adults	uIL-18	Early Diagnosis of AKI, RRT, mortality	uIL-18 was not reliable predictor of AKI but did predict composite outcome of death and RRT within 28 days

AKI; Acute kidney injury, ICU;Intensive care unite, LOS;length of stay, RRT;renal replacement therapy, pNGAL; plasma neutrophil gelatinase associated lipocalin, uNGAL; urine neutrophil gelatinase associated lipocalin, uKIM-1; urine kidney injury molecule -1, uL-FABP; urine liver fatty acid binding protein, N-acetyl β-DG; N-acetyl β-Dglucosaminidase, CRE;creatinine, AUC;under curve area, eGFR; estimated glomerular filtration rate