Appendix Table 3.
Biomarker AKI Prognostic Studies
| Clinical Settings | Authors and Year of Publication | Biomarkers | Sample Size | Study Design | Patient Type at Time of Biomarker Measurement | Serial Biomarkers | End Point | Summary of Findings |
| ICU | Parr et al. (62), 2015 | uL-FABP, uIL-18, uKIM-1, uNGAL | 152 adults | Prospective, single-center | Stage 1 AKI | No | Composite outcome was comprised of persistent doubling of sCR (≥2 d), dialysis, and mortality | AUCs for predicting composite outcome (uL-FABP 0.79, uIL-18 0.64, uKIM-1 0.62, uNGAL 0.65, and combination of biomarkers 0. 81). Clinical-model AUCs for composite outcome was 0.74; adding uL-FABP to clinical model improved AUC (0.82), NRI (31%) and IDI (0.09). |
| Pike et al. (73), 2015 | IL-6, IL-8, IL-10, IL-18, MMIF, TNFR-I, TNFR-II, DR-5 | 817 adults | Prospective, nested observational cohort, multicenter | AKI with RRT | No | Renal recovery was defined as being alive and independent from RRT by day 60 after hospital discharge; 60-d mortality | AUCs for renal recovery (IL-6 0.61, IL-8 0.63, IL-10 0.57, IL-18 0.58, MIF 0.57). Clinical-model AUCs for renal recovery (0.73) and mortality (0.74); Adding IL-8 to clinical model improved the prediction of renal recovery and mortality (AUCs 0.76 and 0.78, respectively). IL-8 improved IDI and NRI for renal recovery and mortality. | |
| Koyner et al. (83), 2015 | uTIMP-2*IGFBP7 | 692 adults | Prospective, multicenter | No AKI/stage 1 AKI | No | 9-mo composite endpoint of all-cause mortality and/or RRT | UTIMP-2*IGFBP7>2.0 and sCR showed (adjusted HRs of 2.16 and 1.40, respectively) for death or RRT within 9 mo; Clinical model + uTIMP-2*IGFBP7 did not improved AUC (0.70), but did improve NRI by 23% and IDI (0.01). | |
| Koyner et al. (119), 2015 | uNGAL, pNGAL, uKIM-1, uIL-18, uTIMP-2*IGFBP7, FST | 77 adults | Prospective, multicenter | Stage 1/stage 2 AKI | No | Progression to AKIN stage 3, need of RRT, mortality | AUCs for prediction of progression to AKI stage 3 (uNGAL 0.65, pNGAL 0.75, uKIM-1 0.63, uIL-18 0.65, uTIMP-2*IGFBP7 0.69, and FST 0.87), Combining FST with uTIMP-2*IGFBP7 resulted in nonsignificant improvement in AUC 0.90. FST (2 h urine output) had AUCs of 0.86 and 0.70 for RRT and mortality. | |
| Dewitte et al. (75), 2015 | uTIMP-2*IGFBP7, pNGAL | 57 adults | Prospective, single-center | Stage 1/stage 2/stage 3 | Yes (at inclusion and 24 h) | Recovery defined as return to sCR<1.5×baseline or 0.35 mg/dl above the baseline with reversal of oliguria within 48 h; major adverse kidney events was defined as death, RRT, or persistence of renal dysfunction (sCR≥200% above baseline) at hospital discharge | uTIMP-2*IGFBP7 and pNGAL AUCs for early renal recovery (0.70 and 0.78, respectively); uTIMP-2*IGFBP7 showed good ability to predict major adverse kidney events, with AUC-ROC values close to 0.8; where as pNGAL had AUCs 0.68–0.76. Clinical Model AUC for renal recovery was 0.87; adding uTIMP-2*IGFBP7+pNGAL to clinical model improved AUC (0.89), NRI, and IDI. | |
| Murugan et al. (74), 2014 | IL-1β, IL-6, IL-8, IL-10, IL-18, MIF, TNF, TNFR-I, TNFR-II, DR-5, GM-CSF | 817 adults | Prospective, nested observational cohort, multicenter | AKI with RRT | No | Renal recovery was defined as being alive and independent from RRT by day 60 after hospital discharge; 60-d mortality | Increased concentrations of plasma IL-8, IL-18, MIF, and TNFR-I were associated with slower renal recovery and increased mortality. | |
| Aregger et al. (120), 2014 | uIGFBP7, pNGAL | 64 adults (includes 12 adults as control) | Prospective, multicenter | Stage 1/stage 2/stage 3 | No | Predicting early recovery (defined as not classifying for any RIFLE class during 7-d follow-up), RRT, mortality | AUCs of uIFGBP-7 for early recovery 0.74, need of RRT 0.65, 30-d mortality 0.65 and in-hospital mortality 0.68. Addition of uIGFBP-7 to clinical model improved prediction of renal recovery from 76.6%–82.1% concordant values (IDI: 0.081±0.04). Clinical Model + uIGFBP-7+pNGAL did not improved AUCs. | |
| Yamashita et al. (121), 2014 | uTIMP-2, uNAG, pNGAL, pIL-6 | 98 adults | Prospective, single-center | No AKI/stage 1/stage 2 | No | AKI was defined on the basis of KDIGO criteria; progression of AKI stage (non-AKI to AKI any stage, stage 1–2, stage 2–3) | AUCs for prediction of severe AKI: uTIMP-2, 0.80; pNGAL, 0.87; pIL-6, 0.70; uNAG, 0.83; and progression of AKI: uTIMP-2, 0.73; pNGAL, 0.76; pIL-6, 0.74; uNAG, 0.77. uTIMP-2 showed the highest AUCs for 7-d (0.83) and in-hospital mortality (0.74), whereas sCR had AUCs of 0.67 and 0.61, respectively. AUC of the clinical model for severe AKI was 0.87; adding uTIMP-2 to the clinical model improved AUC (0.89), NRI (41%), and IDI (0.04). | |
| Kashani et al. (23), 2013 | uTIMP-2*IGFBP7, uKIM-1, IL-18, uL-FABP, uNGAL, pNGAL, pCys-C, π-GST | 522 adults (discovery) | Prospective, multicenter | No AKI/stage 1 AKI | No | MAKE30 includes death, dialysis and persistent renal dysfunction (sCR ≥ 200% above baseline at hospital discharge) | MAKE30 elevated sharply for uTIMP-2*IGFBP7 above 0.30 and doubled for values above 2.0. | |
| 728 adults (validation) | ||||||||
| Zhang et al. (122), 2012 | sCys-C | 232 adults | Retrospective, single-center | AKI with RRT | No | Renal recovery was defined as dialysis independence and final sCR<50% above baseline value | sCys-C showed better performance in predicting renal function recovery than sCR (AUC, 0.87 versus 0.63; P<0.01). | |
| Srisawat et al. (72), 2011 | uNGAL, uCys-C, uIL-18, uHGF, uNGAL/MMP-9, and urinary creatinine | 76 adults | Prospective, multicenter | AKI with RRT | Yes (days 1, 7, and 14) | Renal recovery was defined as alive and free of dialysis at 60 d from the start of RRT | AUC for renal recovery: uNGAL, 0.70; uCys-C, 0.61; uIL-18, 0.42; uHGF, 0.74; uNGAL/MMP-9, 0.53; urinary creatinine, 0.66. Clinical model had an AUC of 0.74; clinical model + relative change of uHGF + uNGAL + uCys-C + uNGAL/MMP-9+uIL-18 improved AUC (0.94) and NRI (63.3%). | |
| Lorenzen JM et al. (102), 2011 | mRNAs (transcriptome) | 77 adults, 30 age-matched controls | Prospective, single-center | AKI with RRT | No | Survival 4 wk after initiation of AKI | MIR-210 was identified as an independent prognostic factor for 28-d survival with AUC of 0.7 (95% CI, 0.53 to 0.78; P=0.03), PPV 0.41, and NPV 1.0. | |
| Kumpers et al. (123), 2010 | pNGAL | 109 adults | Prospective, single-center | AKI with RRT | Yes | Renal recovery was defined as no need for RRT at day 28 after the study enrollment, mortality | AUCs for predicting 14-d mortality: pNGAL, 0.74; cut-off, 360 ng/ml); no association was found between renal recovery and pNGAL. | |
| Cardiac surgery | Moledina et al. (124), 2015 | pNGAL | 1191 adults | Prospective, multicenter | No AKI | Yes (preoperative, 0–6 h, peak 1–3 d postsurgery) | All-cause mortality (3-y follow-up) | Elevated first preoperative and postoperative pNGAL levels were significantly associated with mortality (adjusted HR, 1.48 and 1.31, respectively; 3rd tertile versus first tertile). No association persists between postoperative NGAL and mortality after adjusting for perioperative sCR changes. |
| Arthur et al. (22), 2014 | uL-FABP, uIL-18, uKIM-1, uNGAL, 32 biomarkers | 95 adults | Prospective, multicenter | Stage 1 AKI | No | AKI progression was defined as worsening of renal dysfunction (AKIN stage 1 to a higher AKIN stage 2/3) within 10 d or mortality within 30 d; secondary outcome was AKIN stage 3 or death | AUCs for primary and secondary outcomes: clinical model, 0.63 and 0.68; uIL-18, 0.74 and 0.89; uL-FABP, 0.67 and 0.85; uKIM-1, 0.73 and 0.81; uNGAL, 0.72 and 0.83. Combination of uIL-18 and uKIM-1 improves prediction of AKIN-3 or death with an AUC of 0.93. | |
| Coca et al. (82), 2014 | uL-FABP, uIL-18, uKIM-1, uNGAL, albumin | 1199 adults | Prospective, multicenter | No AKI | Yes (preoperative, 0–6 h postoperative, daily for up to 5 d) | 3-y mortality | Among patients with AKI, adjusted HRs for 3-year mortality for individual urinary biomarkers were: uNGAL, 2.52; uIL-18, 3.16; uKIM-1, 2.01; uL-FABP, 2.35 and urine albumin 2.85 (highest tertile versus lowest tertile). Addition of uIL-18, uL-FABP, and uKIM-1 to clinical model did not change AUC (0.69–0.71), but improved NRI (44%, 44%, and 18%, respectively). | |
| Meersch et al. (125), 2014 | uTIMP-2*IGFBP7, pNGAL | 50 adults | Prospective, single-center | No AKI | Yes (preoperative, 4 h, 12 h, and 24 h after CPB) | Renal recovery was defined as sCR value at hospital discharge equal to or lower than the preoperative creatinine value | AUCs for prediction of renal recovery for uTIMP-2*IGFBP7 was 0.79. Combination of NGAL and uTIMP-2*IGFBP7 did not improve AUC. | |
| Alge et al. (21), 2013 | Urinary angiotensinogen | 97 adults | Prospective, single-center | Stage 1 AKI | No | Progression to a higher AKIN stage, AKIN stage 3, RRT, mortality | uAnCR AUCs for worsening of AKI (0.70), AKIN stage 3 (0.71), RRT (0.71), AKIN 3 or mortality (0.75) and RRT or mortality (0.71). Prognostic predictive power of uAnCR was improved when only patients with AKIN stage 1 were analyzed. Adding uAnCR to clinical model improved prediction of worsening of AKI (NRI, 45.7%). | |
| Kidney transplant | Hall et al. (126), 2010 | uNGAL, IL-18, KIM-1 | 91 adults | Prospective, single-center | Transplant | Yes (0 h, 6 h, 12 h, 18 h, 1st, and 2nd postoperative day) | Graft recovery was defined in three categories: DGF, SGF, and IGF; RRT within 1 wk of kidney transplant | AUCs for predicting dialysis: uNGAL 0.82, IL-18 0.82; whereas KIM-1 had poor prediction (AUC 0.50); Clinical model + uNGAL+ IL-18 did improve reclassification by 110% (P<0.001). |
| Reese et al. (127), 2015 | uNGAL, uKIM-1, uIL-18, uL-FABP, urinary microalbumin | 2441 adults | Prospective, multicenter | Transplant | No | DGF was defined as a requirement for RRT within 7 d after transplant, 6-mo eGFR | High donor uNGAL levels were significantly associated with recipient DGF with RR 1.21 (highest versus lowest tertiles). Addition of urinary biomarkers does not improve AUC, IDI, and NRI. At 6-mo, donor urinary biomarkers added minimal value in predicting recipient allograft function. | |
| Pianta et al. (128), 2015 | uTIMP-2*IGFBP7, VEGF-A, MMIF, MCP-1, TFF3, CXCL16, sCR | 56 adults | Prospective, single-center | Transplant | Yes (4 h, 8 h, and 12 h) | DGF was defined as requirement for RRT within 7 d | AUCs for predicting DGF: uTIMP-2*IGFBP7, 0.76; VEGF-A, 0.81; uTIMP-2, 0.73; and uIGFBP7, 0.71; whereas sCR showed poor prediction for DGF (AUC 0.56). Clinical model AUC for DGF was 0.70; adding TIMP-2 (0.81 and 0.11) and VEGF-A (0.85 and 0.19) separately to clinical model improved AUC and IDI. | |
| Hospitalized | Wang et al. (129), 2015 | uL-FABP | 114 adults | Prospective, single-center | Stage 3 AKI | No | Recovery was defined as alive and neither requiring RRT nor having persistent AKIN 3 with a minimum crcl of 20 mL/min at hospital discharge | AUCs for renal recovery: uL-FABP, 0.91; sensitivity, 85.5; and specificity, 86.4% for cut-off 102.1 ng/mg). uL-FABP modestly predicted hospital death (AUC, 0.83) and RRT (AUC, 0.71). u-FABP improved renal recovery classification compared with clinical model (NRI, 35%; P=0.02) |
| Westhoff et al. (130), 2015 | uTIMP-2*IGFBP7 | 46 children | Prospective, single-center | Stage 1/stage 2/stage 3 | No | Predicting mortality and need of RRT | AUCs for 30-d and 90-d mortality: uTIMP-2*IGFBP7, 0.79 and 0.84, respectively). AUC for RRT was 0.67. | |
| Singer et al. (63), 2011 | uNGAL | 145 adults | Prospective, single-center | Stage 1/stage 2/stage 3 | No | Progression to a higher AKIN stage, dialysis, mortality within 7 d of ICU admission; type of AKI | uNGAL had an AUC of 0.71 (95% CI, 0.62 to 0.8), as compared with sCR level, which had an AUC of 0.61 (95% CI, 0.51 to 0.71). | |
| Srisawat et al. (89), 2011 | pNGAL | 189 adults | Prospective, multicenter | Stage 3 | No | Recovery was defined as alive and not requiring RRT during hospitalization and nor having a persistent RIFLE-F classification at hospital discharge | pNGAL AUCs for renal recovery was 0.74. Clinical model + pNGAL did not improve AUC, but did improve NRI by 17%. | |
| Cirrhosis | Belcher et al. (24), 2014 | uL-FABP, uIL-18, uKIM-1, uNGAL | 188 adults | Prospective, multicenter | Stage 1/stage 2/stage 3 | Yes (daily for 3 d) | Progression to a higher AKIN stage, dialysis, mortality | AUCs for AKI progression and death: uL-FABP, 0.76; uIL-18, 0.71; uKIM-1, 0.66; uNGAL, 0.77. IL-18 independently improved NRI (51%). |
| Heart Failure | Verbrugge et al. (131), 2013 | uIL-18, uKIM-1, uNGAL | 83 adults | Prospective, single-center | No AKI | No | Persistent renal impairment was defined as persistently elevated sCR levels (≥0.3 mg/dl) after 6 mo compared with baseline; all-cause mortality | uIL-18 was a predictor of persistent renal impairment with an AUC of 0.67. uIL-18 was also associated with all-cause mortality (HR 1.48). |
uL-FABP, urinary liver-type fatty acid–binding protein; uIL-18, urinary IL-8; uKIM-1, urinary kidney injury molecule-1; uNGAL, urinary neutrophil gelatinase–associated lipocalin; sCR, serum creatinine; AUC, area under curve; NRI, net-reclassification index; IDI, integrated discrimination improvement; MMIF, macrophage migration inhibitory factor; TNFR-I, TNF receptor 1; TNFR-II, TNF receptor II; DR-5, death receptor-5; MIF, migration inhibitory factor; uTIMP-2, urinary tissue inhibitor of metalloproteinases-2; IGFBP7, IGF-binding protein 7; pNGAL, plasma neutrophil gelatinase–associated lipocalin; uIL-18, urinary IL-18; FST, furosemide stress test; AKIN, Acute Kidney Injury Network; AUC-ROC, area under the receiver operating characteristic curve; GM-CSF, granulocyte macrophage stimulating factor; RIFLE, risk, injury, failure, loss of kidney function, and ESRD; uIGFBP7, urinary IGF-binding protein 7; uNAG, urinary n-acetyl-β-d-glucosaminidase; pIL-6, plasma IL-6; KDIGO, Kidney Disease Improving Global Outcomes; pCys-C, plasma cystatin-C; π-GST, π-glutathione s-transferase; MAKE, major adverse kidney events; sCys-C, serum cystatin-C; uHGF, urinary hepatocyte growth factor; MMP-9, matrix metalloproteinase-9; NPV, negative predictive value; CPB, cardio-pulmonary bypass; HR, hazard ratio; NGAL, neutrophil gelatinase–associated lipocalin; uAnCR, urinary-angiotensinogen-creatinine ratio; DGF, delayed graft function; SGF, slow graft function; IGF, immediate graft function; KIM-1, kidney injury molecule-1; RR, relative risk; VEGF-A, vascular endothelial growth factor-A; MCP-1, monocyte chemotactic protein 1; TFF3, trefoil factor 3; CXCL16, chemokine (c-x-c motif) ligand 16; TIMP-2, tissue inhibitor of metalloproteinases-2; crcl, creatinine clearance; ICU, intensive care unit.