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. 2022 Apr 7;10:842544. doi: 10.3389/fped.2022.842544

TABLE 4.

Neonatal acute kidney injury biomarkers.

Biomarker Properties and production Notable Studies
Authors and year Findings
Cystatin C (CysC) Cysteine protease produced at a constant rate by all nucleated cells Hidayati et al. (94) • Cys-C based estimated GFR to diagnose AKI
    ° Sensitivity: 84.8%
    ° Specific: 61.8%
    ° PPV: 41.8%
    ° NPV: 89.7%
• AUC for CyC: 84.9%
• Optimal cut-off for CysC: 1.605 mg/L
Lagos-Arevalo et al. (95) • Early ICU CysC predicted SCr-based AKI development
    • AUC 0.70; 95% CI 0.53–0.89
Li et al. (96) • uCysC independently associated with AKI
    • OR 2.07, AUC 0.92
Sarafidis et al. (97) • Asphyxiated neonates had significantly higher
    ° sCysC on DOL 1 (2.86 mg/L (IQR 2.1–3.0) vs. 2.23 (1.75–2.62);
p = 0.049)
    ° uCysC at all time points
Compared to non-asphyxiated infants
• Urine CysC cut-off > 476 ng/mg:
    ° AUC 0.927, p < 0.001
    ° Sensitivity 100%
    ° Specificity 83.3%
• Urine CysC cut-off > 204.4 ng/mL:
    ° AUC 0.937, p < 0.001
    ° Sensitivity 100%
    ° Specificity 91.7%
Askenazi et al. (98) Maximum CysC levels did not differ between those with and without AKI nor between survivors and non-survivors
Neutrophil gelatinase-associated lipocalin (NGAL) Protein expressed by multiple tissues including kidney Sarafidis et al. (99) • uNGAL significantly higher in those with AKI compared to those without AKI on day AKI diagnosed by SCr
• uNGAL had no significant ability to predict AKI in 1–2 days prior to AKI development
Tabel et al. (100) • Median uNGAL significantly higher in preterm infants with AKI than those without AKI on DOL 1 and 7
• uNGAL independently associated with AKI
Sarafidis et al. (97) • Asphyxiated neonates had significantly higher sNGAL and uNGAL at all time points compared to non-asphyxiated neonates
• sNGAL was significantly higher in asphyxiated infants with AKI compared to non-asphyxiated neonates at all time points, asphyxiated infants with AKI and asphyxiated infants without AKI on DOL 1 and 3
• Serum NGAL cut-off > 89.6 ng/mL:
    ° AUC: 0.942, p < 0.001
    ° Sensitivity 100%
    ° Specificity 92.3%
• uNGAL was significantly higher in asphyxiated infants with AKI compared to non-asphyxiated infants at all time points and in asphyxiated infants without AKI and non-asphyxiated infants at DOL 10
• uNGAL cut-off > 39.3 ng/mg:
    ° AUC 0.896, p < 0.001
    ° Sensitivity 100%
    ° Specificity 83.3%
• uNGAL cut-off > 18.61 ng/mL:
    ° AUC 0.865, p < 0.001
    ° Sensitivity 100%
    ° Specificity 83.3%
Krawczeski et al. (101) • In term neonates requiring CPB, pNGAL and uNGAL significantly higher at 2 h after CPB and remained elevated for 48 h post-operatively in patients with AKI
• NGAL 2-hour after CPB the earliest and strongest predictor of AKI
Askenazi et al. (98) • Compared to those without AKI, those with AKI had higher max NGAL
    • AKI: 985 ng/mL (95% CI 452, 1,398)
    • No AKI: 458 ng/mL (95% CI 210, 587)
    • For every 100 ng/mL rise in NGAL, the odds of AKI increased by 20%
    ° OR 1.2 (1.0–1.6), p < 0.01
    ° AUC 0.80
    • Combining NGAL and OPN improved ability to detect AKI
    ° AUC 0.90
• No difference in NGAL concentrations between survivors and non-survivors
Interleukin-18 (IL-18) Pro-inflammatory cytokine induced in proximal tubule after AKI and renal tubular injury Li et al. (96) • uIL-18 independently associated with AKI in non-septic critically ill neonates
    ° OR 2.27, AUC 0.72
Askenazi et al. (98) Maximum IL-18 levels did not differ between those with and without AKI nor between non-survivors vs. survivors
Kidney injury molecule-1 (KIM-1) type 1 transmembrane protein that has been found to be highly upregulated in the proximal tubule epithelial cells; secreted in urine after AKI Askenazi et al. (98) • Maximum KIM-1 levels did not differ between those with and without AKI
• Compared to survivors, non-survivors had higher KIM-1
    ° Non-survivors: 385 pg/mL (95% CI 231, 1,028)
    ° Survivors: 264 (95% CI 147, 549)
    ° For every 100 pg/mL rise in KIM-1, there was a 10% higher odds of
death (OR 1.1 (1.0–1.2), p < 0.02; AUC 0.64)
Sarafidis et al. (97) • Higher absolute uKIM-1 levels in asphyxiated neonates on DOL 10
• uKIM-1 was comparable between those with asphyxia and AKI, those with asphyxia but no AKI, and non-asphyxiated infants at all time points
Osteopontin (OPN) Cytokine expressed and upregulated during inflammation and AKI Askenazi et al. (98) • Compared to subjects without AKI, those with AKI had higher OPN
    ° AKI: 468 ng/mL (95% CI 247, 655)
    ° No AKI: 217 ng/mL (95% CI 115, 280)
    ° For every 100 ng/mL rise in OPN, the odds of AKI increased by 220%
(OR 3.2 (1.5–9.9), p < 0.01; AUC 0.83)
    ° Combining NGAL and OPN improved ability to detect AKI (AUC 0.90)
• Compared to survivors, non-survivors had higher maximum OPN
    ° Non-survivors: 482 ng/mL (95% CI 281, 631)
    ° Survivors: 20 ng/mL (95% CI 112, 371)
    ° For every 100 ng/mL rise in OPN, there was a 80% higher odds of
death (OR 1.8 (1.2–2.7), p < 0.001; AUC 0.78)
Beta-2 microglobulin (B2mG) Peptide produce from cellular membrane turnover, particularly elevated with tubular dysfunction or injury Abdullah et al. (102) • In term asphyxiated neonates, uB2mG levels were significantly higher in infants with AKI compared to those without AKI and were found to be predictive of AKI within the first 24 h after asphyxiation
    ° AKI: 6.8 mg/L vs. no AKI: 2.6 mg/L, p < 0.001
    ° AUC: 0.944
    ° Ideal cut off: 3.8 mg/L
        • 81% sensitive
        • 81.6% specific
Askenazi et al. (98) Maximum B2mG levels did not differ between those with and without AKI nor between non-survivors vs. survivors

GFR, glomerular filtration rate; AKI, acute kidney injury; PPV, positive predictive value; NPV, negative predictive value; AUC, area under the curve; mg/L, milligrams per liter; ICU, intensive care unit; SCr, serum creatinine; uCysC, urine Cystatin C; sCysC, serum Cystatin C; DOL, day of life; IQR, interquartile range; uNGAL, urine neutrophil gelatinase lipocalin; sNGAL, serum neutrophil gelatinase lipocalin; CPB, cardiopulmonary bypass; pNGAL, plasma neutrophil gelatinase lipocalin; h, hours; ng/mL, nanograms per milliliter; CI, confidence interval; uIL-18, urine interleukin-18; OR, odds ratio; pg/mL, picograms per milliliter; uKIM-1, urinary kidney injury molecule-1; uB2mG, urine Beta-2 microglobulin.