Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

J Pediatr. 2022 Feb;241:133-140.e3. doi: 10.1016/j.jpeds.2021.08.090. Epub 2021 Sep 20.


Objective: To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.

Study design: We performed a multicenter prospective observational study of 64 neonates. Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria.

Results: AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0-5] days vs 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; P = .012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction. KIM-1 had the best predictive performance across time points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life.

Conclusions: Urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving therapeutic hypothermia who developed AKI. However, wide variability and unclear cutoff levels make their clinical utility unclear.

Keywords: acute kidney injury; cystatin C; hypoxic ischemic encephalopathy; insulin-like growth factor–binding protein 7; interleukin-18; kidney injury molecule-1; neutrophil gelatinase-associated lipocalin; tissue inhibitor of metalloproteinases 2.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / diagnosis*
  • Acute Kidney Injury / urine*
  • Biomarkers / urine
  • Cystatin C / urine
  • Female
  • Hepatitis A Virus Cellular Receptor 1 / analysis
  • Humans
  • Hypothermia, Induced*
  • Hypoxia-Ischemia, Brain / therapy*
  • Infant, Newborn
  • Insulin-Like Growth Factor Binding Proteins / urine
  • Interleukin-18 / urine
  • Lipocalin-2 / urine
  • Male
  • Prospective Studies
  • Tissue Inhibitor of Metalloproteinase-2 / urine
  • Vasoconstrictor Agents / administration & dosage


  • Biomarkers
  • Cystatin C
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • Insulin-Like Growth Factor Binding Proteins
  • Interleukin-18
  • Lipocalin-2
  • TIMP2 protein, human
  • Vasoconstrictor Agents
  • insulin-like growth factor binding protein-related protein 1
  • Tissue Inhibitor of Metalloproteinase-2