Appendix Table 2.
Biomarkers Studies for Early Diagnosis of AKI
| Clinical Settings | Authors and Year of Publications | Biomarkers | Sample Size | Study Design | Serial Biomarkers | End Point (Urine/Serum) | Summary of Findings |
| ICU | Bell et al. (105), 2015 | uTIMP-2*IGFBP7, uNGAL, uCys-C | 94 adults | Prospective, single-center | No | KDIGO stage 1, 2, and 3 within 48 h | AUCs for prediction of AKI by uTIMP-2*IGFBP7, uNGAL, and uCys-C were 0.40, 0.51, and 0.43, respectively. |
| Zwiers et al. (106), 2015 | uNGAL, uKIM-1 | 100 children (age 1 d to 1 yr) | Prospective, single-center | Yes (0–6 h, 6–12 h, 12–24 h, 24–36 h, 36–48 h, and 48–72 h) | RIFLE criteria within 48 h after ICU admission | AUCs for predicting AKI: uNGAL: 0–6 h, 0.81; 6–12 h, 0.78; 12–24 h, 0.71; 24 h peak level, 0.81; uKIM-1: at 12–24 h, 0.74. | |
| Wong et al. (107), 2015 | ELA2, FGF13, MMP-8, OLFM4, PRTN3 | 241 children (derivation); 200 children (validation) | Prospective, multicenter | No | Modified KDIGO stage 2 classification (at least 2-fold increase of sCR from baseline serum creatinine), mortality | Multibiomarker-based model to predict SAKI at day 3 had an AUC of 0.95 (95% CI, 0.91 to 0.99) in derivation and 0.83 (95% CI, 0.72 to 0.95) in test cohort. AUC of SAKI risk model to predict mortality was 0.90 (95% CI, 0.85 to 0.96). | |
| Bihorac et al. (38), 2014 | uTIMP-2*IGFBP7 | 408 adults | Prospective, multicenter | No | KDIGO Stage 2 and 3 criteria within 12 h after the enrollment | AUCs for predicting AKI for uTIMP-2*IGFBP7, 0.82; sCR, 0.63. Clinical model had an AUC of 0.70; clinical model + uTIMP-2*IGFBP7 improved AUC to 0.86. Patients with uTIMP-2*IGFBP7 values between 0.3 and 2.0 had 5-fold risk of AKI whereas it was 17-fold for value above 2.0. | |
| Frank AJ et al. (100), 2012 | GWAS | 1264 adults (887 with genotype data) | Retrospective, single-center | No | 0.3 mg/dl or ≥50% increase in sCR from baseline in the first 72 h after ICU admission | 2 SNPs in the B-cell CLL/Lymphoma 2 (BCL2): rs8094315 (OR 0.68 per additional copy of minor G allele; P<0.01) and rs12457893 gene (OR 0.68 per additional copy of minor C allele; P<0.01) and a SNP in the serpin peptidase inhibitor, clade A (α-1 antiproteinase, antitrypsin), member 4 (SERPINA4) gene: rs2093266 (OR 0.53 per additional copy of minor A allele; P<0.01) were associated with a decreased risk of developing AKI. | |
| Kashani et al. (23), 2013 | uTIMP-2*IGFBP7, uKIM-1, IL-18, uL-FABP, uNGAL, pNGAL, pCys-C, α-/π-GST | 522 adults (discovery) | Prospective, multicenter | No | Three KDIGO stage 2 and 3 criteria within 12 h of sample collection | AUCs for predicting AKI: uTIMP-2*IGFBP7, 0.80; IGFBP7, 0.76; uTIMP-2, 0.79; sCR, 0.75. Clinical-model AUC for AKI stage 2/3 was 0.81. Clinical model + uTIMP-2*IGFBP7 improved AUC to 0.87, IDI to 0.08, and NRI to 68%. | |
| 728 adults (validation) | |||||||
| Nejat et al. (35), 2010 | pCys-C, sCR | 444 adults | Prospective, multicenter | Yes (0 h, 12 h, 24 h, and daily for the next 6 d) | AKIN criteria (50% or 0.3 mg/dl increase in sCR), sustained AKI, dialysis, and mortality within 30 d | AUCs for predicting AKI: pCys-C, 0.78; sCR ,0.87. pCys-C predicted sustained AKI (AUC, 0.80) and need of dialysis or death (AUC, 0.68). | |
| Siew et al. (37), 2010 | uIL-18 | 451 adults | Prospective, single-center | No | AKIN criteria (50% or 0.3 mg/dl increase in sCR), AKI severity, dialysis within 28 d, mortality | AUCs for predicting AKI (uIL-18: at 24 h 0.62, 48 h 0.60, AKIN stage 1 0.59, AKIN stage 2/3 0.62). uIL-18 independently predicts need of dialysis or death (OR 1.86). Addition of uIL-18 did not improve ability of uNGAL to predict AKI as assessed by change in AUC curve. | |
| Cruz et al. (34), 2010 | pNGAL | 301 adults | Prospective, single-center | Yes (daily for 4 d) | RIFLE criteria, need of dialysis during ICU stay | AUCs for predicting AKI within 48 h (pNGAL 0.78, sensitivity 73%, specificity 81%, cut-off 150 ng/ml). pNGAL was good predictor for RRT (AUC 0.82); whereas moderate predictor for ICU mortality (AUC 0.67). | |
| Siew et al. (32), 2009 | uNGAL | 451 adults | Prospective, single-center | No | AKIN criteria (50% or 0.3 mg/dl increase in sCR), dialysis within 28 d, mortality | AUCs for predicting AKI: clinical model, 0.81; uNGAL at 24 h, 0.71; 48 h, 0.64; clinical model + uNGAL, 0.82. uNGAL independently predicts severe AKI during hospitalization (HR, 2.6). | |
| Cardiac surgery | Elmariah S et al. (99), 2016 | Mass spectrometry (metabolite profiling) | 44 adults | Prospective, single-center | No | Increase in plasma creatinine to 150%–199% of baseline or increase of ≥0.3 mg/dl within 7 d of TAVR | Baseline levels of 5‐adenosylhomocysteine predicted AKI after adjustment for eGFR (OR per 1 SD increase, 5.97; 95% CI, 1.62 to 22.0; P<0.001). |
| Zacharias et al. (104), 2015 | NMR spectra | 85 adults | Prospective single-center | No | AKIN staging 1,2, and 3 | A random forests classifier prognosticated AKI across all stages with an average accuracy of 80±0.9% and an AUC of 0.87. | |
| Torregrosa et al. (108), 2015 | uNGAL, uKIM-1, uL-FABP | 193 adults | Prospective, single-center | No | RIFLE criteria | In coronary angiography group, AUCs for predicting AKI: uNGAL, 0.96; uKIM-1, 0.71, whereas L-FABP had poor prediction. In CABG group, AUCs for predicting AKI: uNGAL, 0.92; uKIM-1, 0.72; and uL-FABP, 0.74. | |
| Zhang et al. (109), 2015 | IL-6, IL-10 | 960 adults | Prospective, multicenter | Yes (preoperative and daily up to day 5) | AKIN criteria (50% or 0.3 mg/dl increase in sCR from baseline), severe AKI, all-cause mortality | Elevated first postoperative IL-16 and IL-10 were significantly associated with AKI (OR, 2.13 and 1.57, respectively; 3rd tertile versus 1st tertile). Elevated IL-10 was associated with lower risk of mortality (adjusted HR, 0.72). | |
| Meersch et al. (110), 2014 | uTIMP-2*IGFBP7, uNGAL, uKIM-1 | 51 children | Prospective, single-center | Yes (preoperative, 4 h, and 24 h after initiation of CPB) | RIFLE criteria within 72 h after surgery | AUCs for predicting AKI: uTIMP-2*IGFBP7, 0.85; uNGAL, 0.87; and uKIM-1, 0.64. Adding uTIMP-2*IGFBP7 to clinical model improved AKI risk prediction significantly (P<0.001). | |
| Pilarczyk et al. (111), 2015 | uTIMP-2*IGFBP7 | 60 adults | Prospective, single-center | Yes (4 h after surgery and then every 12 h up to 4 d) | KDIGO stage 2 or 3 within 48 h after surgery | AUC for predicting AKI stage 2/3: uTIMP-2*IGFBP7, 0.86, whereas sCR had poor prediction (AUC, 0.36). | |
| Ho et al. (112), 2015 | NGAL, KIM-1, NAG, Cys-C, IL-18, L-FABP, Hepcidin-25, uTIMP-2, uIGFBP7, u-α-GST, u-π-GST | 28 studies | Meta-analysis | — | RIFLE (eight studies), AKIN (16 studies), or KDIGO criteria three studies); 1 study used combined AKIN/RIFLE | Composite AUCs for AKI: NGAL, KIM-1, and L-FABP, 0.72; and Cys-C, IL-18, u-α-GST, u-π-GST, <0.70). | |
| Sabbisetti et al. (113), 2014 | Blood KIM-1, uKIM-1 | 92 adults | Prospective, single-center | No | KDIGO criteria within 48 h | AUCs for predicting AKI: blood KIM-1, 0.96; normalized uKIM-1, 0.98; uKIM-1, 0.91. | |
| Koyner et al. (114), 2013 | uCys-C | 1203 adults, 299 children | Prospective, multicenter | Yes (preoperative, 0–6 h, and 6–12 h postoperative) | AKIN criteria (50% or 0.3 mg/dl increase in sCR), severe AKI (doubling of sCR or need of dialysis) | uCys-C was not associated with the development of AKI after cardiac surgery in both adults and children. Addition of uCys-C to clinical model did not significantly increase AUC (adults: mild AKI: clinical model, 0.67; uCys-C, 0.68; clinical model + uCys-C, 0.68; severe AKI clinical model, 0.72; uCys-C, 0.71; clinical model + uCys-C, 0.72). | |
| Parikh et al. (115), 2013 | uKIM-1, uL-FABP, uNGAL, uIL-18 | 1219 adults, 311 children | Prospective, multicenter | Yes (preoperative and every 6 h for the first 24 h after surgery) | AKIN stage 2/RIFLE-I or dialysis, progression to higher stage, mortality | Clinical model for AKI had an AUC of 0.69 in adults and 0.78 in children. Addition of uKIM-1 to clinical model marginally improved discrimination and classification in adults (AUC, 0.73; NRI, 19%). uKIM-1 and uL-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (uNGAL and uIL-18). | |
| Parikh et al. (29), 2011 | uNGAL, pNGAL, uIL-18 | 1219 adults | Prospective, multicenter | Yes (preoperative and every 6 h for the first 24 h after surgery) | AKIN stage 2/RIFLE-I or dialysis | AUCs for predicting AKI: clinical model, 0.69; uNGAL, 0.67; pNGAL, 0.70; and uIL-18, 0.74. Adding uIL-18 and pNGAL separately to clinical model improved AUCs (0.76 and 0.75, respectively), NRI, and IDI. | |
| Devarajan P et al. (98), 2010 | SELDI-TOF MS (proteomics) | 30 children (discovery), 365 children (validation) | Prospective, single-center | ≥50% increase in sCR from baseline within 72 h of CPB | AUCs for urine α1-microglobulin, α1-acid glycoprotein, and albumin measured 6 h post-CPB were 0.84 (95% CI, 0.79 to 0.89), 0.87 (95% CI, 0.83 to 0.91), and 0.76 (95% CI, 0.71 to 0.81), respectively. | ||
| Liangos et al. (116), 2009 | uKIM-1, uNAG, uNGAL, uCys-C, uIL-18, urinary α-1 microglobulin | 103 adults | Prospective, multicenter | Yes (preoperative, 2 h, 24 h, and 48 h after discontinuation of CPB) | ≥50% increase in sCR in the first 72 h after termination of CPB | AUCs for predicting AKI: clinical model, 0.83; uKIM-1, 0.78; uNAG, 0.62; uIL-18, 0.66. Adding uKIM-1 to clinical model improved AUC to 0.88. | |
| Bennett et al. (27), 2008 | uNGAL | 196 children | Prospective, single-center | Yes (preoperative, 2 h, 4 h, 6 h, 8 h, 12 h, up to 72 h) | 50% increase in sCR, dialysis, mortality | AUCs for predicting AKI: uNGAL, 0.93 sensitivity, 82%, specificity, 90%, cut-off 100 ng/ml. Need of dialysis: AUC, 0.86; and mortality: AUC, 0.91. | |
| Stafford-Smith et al. (103), 2005 | GWAS | 1671 adults | Prospective, single-center | No | Delta sCR | Two alleles (IL-6 −572C and angiotensinogen 842C) showed a strong association with renal injury in white patients (P<0.001). Adding genetic to clinical factors provided 2–4-fold improvement in prediction of renal injury post–cardiac surgery. | |
| Cardiac catheterization | Hirsch et al. (117), 2007 | uNGAL, pNGAL | 91 children | Prospective, single-center | Yes (precontrast, 2 h, and 6 h) | 50% increase in sCR above baseline | AUCs for predicting CIN at 2 h: uNGAL, 0.92; and pNGAL, 0.91; PPV 100% and 80%; at 6 h: uNGAL, 0.97; and pNGAL, 0.95; PPV 90%; and 100%; for cut-off 100 ng/ml. |
| Hospitalized | Vaidya et al. (18), 2008 | uKIM-1, uIL-18, uNGAL, uNAG, uVEGF, uHGF, uCys-C, uCXCL10 | 204 adults | Cross-sectional | No | a ≥50% increase in sCR from admission value or known baseline, dialysis, mortality | AUCs for predicting AKI: uKIM-1, 0.93; uNAG, 0.83; uNGAL, 0.89; uIL-18, 0.83; uCys-C, 0.85). |
| Ferguson et al. (25), 2010 | uL-FABP | 154 adults | Cross-sectional | No | AKI was defined as a ≥50% increase in sCR from admission value or known baseline, dialysis, mortality | AUC for predicting AKI: uL-FABP, 0.93. uL-FABP was also significant predictor of RRT (P=0.02) and composite end point of death/RRT (P=0.03). Higher levels of uL-FABP were seen in ATN and sepsis AKI, whereas lower levels in contrast nephropathy. | |
| Cirrhosis | Treeprasertsuk et al. (41), 2015 | uNGAL | 121 adults | Prospective, single-center | No | AKIN criteria (50% or 0.3 mg/dl increase in sCR from baseline), 30-d mortality | AUCs for predicting AKI: uNGAL, 0.83; sensitivity, 77.1%; specificity 73.3%; cut-off, 56 ng/ml; baseline sCR, 0.58. In multiadjusted model, uNGAL could not predict 30-d mortality. |
| ICU, NICU, cardiac surgery, cardiac catheterization, hospitalized,ER | Shao et al. (118), 2014 | uKIM-1 | 2979 patients | Meta-analysis (five prospective, two cross-sectional, and four case-control studies) | —- | AKIN/RIFLE/KDIGO | Pooled analysis of studies showed an AUC of 0.86 for prediction of AKI; sensitivity, 74%; and specificity, 86%. |
uTIMP-2, urinary tissue inhibitor of metalloproteinases-2; IGFBP7, IGF-binding protein 7; uNGAL, urinary neutrophil gelatinase-associated lipocalin; uCys-C, urinary cystatin-C; KDIGO, Kidney Disease Improving Global Outcomes; uKIM-1, urinary kidney injury molecule-1; RIFLE, risk, injury, failure, loss of kidney function, and ESRD; ICU, intensive care unit; AUC, area under curve; ELA2,elastase 2; FGF13, fibroblast growth factor 13; MMP-8, matrix metalloproteinases 8; OLFM4, olfactomedin 4; PRTN3, proteinase; sCR, serum creatinine; 95% CI, 95% confidence interval; SAKI, septic acute kidney injury; GWAS, genome-wide association studies; SNP, single-nucleotide polymorphism; OR, odds ratio; uL-FABP, urinary liver-type fatty acid–binding protein; pNGAL, plasma neutrophil gelatinase-associated lipocalin; pCys-C, plasma cystatin-C; α-GST, α-glutathione s-transferase; π-GST, π-glutathione s-transferase; IDI, integrated discrimination improvement; NRI, net-reclassification index; uIL-18, urinary IL-18; AKIN, Acute Kidney Injury Network; HR, hazard ratio; TAVR, transcatheter aortic valve replacement; NMR, nuclear magnetic resonance spectroscopy; CABG, coronary artery bypass graft; NGAL, neutrophil gelatinase-associated lipocalin; NAG, n-acetyl-β-d-glucosaminidase; L-FABP, liver-type fatty acid–binding protein; uIGFBP7, urinary IGF-binding protein 7; u-α-GST, urinary α-glutathione s-transferase; u-π-GST, urinary π-glutathione s-transferase; KIM-1, kidney injury molecule-1; SELDI-TOF MS. surface-enhanced laser desorption/ionization time-of-flight mass spectrometry; CPB, cardio-pulmonary bypass; CIN, contrast nephropathy; PPV, positive predictive value; uVEGF-A, urinary vascular endothelial growth factor-A; uHGF, urinary hepatocyte growth factor; uCXCL10, urinary chemokine (c-x-c motif) ligand 10; ATN, acute tubular necrosis; NICU, neonatal intensive care unit; ER, emergency room.