A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy

Abstract

Background: Current definitions of acute kidney injury (AKI) are not sufficiently sensitive to identify all newborns with AKI during the first week of life.

Methods: To determine whether the rate of decline of serum creatinine (SCr) during the first week of life can be used to identify newborns with AKI, we reviewed the medical records of 106 term neonates at risk of AKI who were treated with hypothermia for hypoxic ischemic encephalopathy (HIE).

Results: Of the newborns enrolled in the study, 69 % showed a normal rate of decline of SCr to ≥50 % and/or reached SCr levels of ≤0.6 mg/dl before the 7th day of life, and therefore had an excellent clinical outcome (control group). Thirteen newborns with HIE (12 %) developed AKI according to an established neonatal definition (AKI-KIDGO group), and an additional 20 newborns (19 %) showed a rate of decline of SCr of <33, <40, and <46 % from birth to days 3, 5, or 7 of life, respectively (delayed rise in estimated SCr clearance group). Compared to the control group, newborns in the other two groups required more days of mechanical ventilation and vasopressor drugs and had higher gentamicin levels, more fluid overload, lower urinary epidermal growth factor levels, and a prolonged length of stay.

Conclusions: The rate of decline of SCr provides a sensitive approach to identify term newborns with AKI during the first week of life.

Keywords: Acute kidney injury; Biomarkers; Epidermal growth factor; Neonate; Serum creatinine.

Fig. 1

Relationship between serum creatinine (Sr Cr or SCr) level, glomerular filtration rate (GFR), and clinical outcome of newborns with hypoxic ischemic encephalopathy (HIE). a Model supporting the hypothesis that the rate of SCr decline can be used as a biomarker to estimate the renal function of term newborns during the first week of life. b Predicted SCr decline in term newborns with a normal or 50 % reduction in GFR. The models shown in a and b were generated based on data reported in previous studies by Schwartz et al. [–15]. c SCr decline in the control group (HIE–Controls) and in the Acute Kidney Injury–Kidney Disease Improved Global Outcome (HIE–AKI–KIDGO) group. d SCr level declines in the control group, while there is a delayed decline in SCr in the newborns with HIE in the delayed rise estimated creatinine clearance (HIE–DReCrCl) group. *p < 0.0001 for all time points (Mann–Whitney test). e–h Compared to the Control group, newborns with HIE in the AKI–KDIGO group and DReCrCl group showed a more prolonged length of hospital stay (e), required more days of mechanical ventilation (f), had higher gentamicin trough levels (g), and required more continuous vasopressor (CVP) drugs (h). *p values for e–g were estimated by analysis of variance (ANOVA) followed by multiple post hoc comparisons whenever appropriate. **p < 0.05 for controls vs. AKI–KDIGO group; ⁺p < 0.05 for DReCrCl group vs. controls; ^#p > 0.05 for AKI–KDIGO group vs. DReCrCl group. *p values for h were estimated by chi-square analysis followed by Bonferroni’s correction whenever appropriate. ** p = 0.0067 for controls vs. AKI–KDIGO group; ^#p = 0.24; for AKI–KDIGO group vs. DReCrCl group; ⁺p = 0.054 for DReCrCl group vs. controls

Fig. 2

Boxplots of changes in blood urea nitrogen (BUN) and urine output in newborns with hypoxic–ischemic encephalopathy (HIE) during the first week of life. The panels show the changes in BUN and urine output (UOP) in control newborns with HIE (Controls), in the acute kidney injury (AKI)–Kidney Disease Improved Global Outcome group (AKI–KDIGO), and in the delayed rise in estimated creatinine clearance group (DReCrCl). The groups were defined as described in detail in the Definition of the study groups, selection of control HIE newborns without AKI, and standard definition of AKI section. p values were estimated by ANOVAwith multiple post hoc comparisons as described in the Statistical analysis section. *p values on 5th day: p < 0.01 for comparisons of both the AKI–KDIGO group vs. controls, and the AKI–KDIGO group vs. DReCrCl group. *p values on 7th day: p < 0.01 for AKI–KDIGO group vs. controls; p < 0.05 for AKI–KDIGO group vs. DReCrCl group

Fig. 3

Receiving operational characteristic (ROC) curves for serum creatinine (SCr), rate of SCr decline, and both SCr + SCr decline combined in newborns with hypoxic–ischemic encephalopathy (HIE). a, b ROC curves generated for SCr levels using samples corresponding to the control group (Control) and acute kidney injury (AKI)–Kidney Disease Improved Global Outcome (AKI-KDIGO) group with HIE (a) or the control group and the delayed rise in estimated creatinine clearance (DReCrCl) group with HIE (b). Pairwise comparisons of ROC curves: a Day 1 vs. day 3, p = 0.0147; day 1 vs. day 5, p = 0.0001; day 3 vs. day 5, p = 0.0125; b Day 1 vs. day 3, p = 0.0116; day 1 vs. day 5, p = 0.0001; day 3 vs. day 5, p = 0.0015. c, d ROC curves generated for SCr decline using samples corresponding to the control group and AKI–KDIGO group with HIE (c) or the control group and DReCrCl group with HIE (d). Pairwise comparisons of ROC curves: c Day 3 vs. day 5, p > 0.05; d Day 3 vs. day 5, p = 0.0441. e Logistic regression analysis was performed to develop ROC curves combining the SCr levels with the rate of SCr decline on days of life 3, 5, and 7, as described in the Methods section. Pairwise comparisons of ROC curves: Day 7 vs. day 3, p = 0.0004; day 7 vs. day 5, p = 0.0350; day 5 vs. day 3, p = 0.0011. Dashed line Reference ROC curve for a test with not discriminatory ability. AUC Area under the curve. The cutoff values, sensitivity, specificity, positive and negative likelihood ratios are reported in Tables 2 and 3. and Electronic Supplementary Material (ESM) Table S2

Fig. 4

Predictive ability of urinary neutrophil associated gelatinase lipocalin (NGAL) and epidermal growth factor (EGF) to diagnose acute kidney injury (AKI) in term newborns with hypoxic–ischemic encephalopathy (HIE) during the first week of life. AKI was defined using the KDIGO + DReCrCl criteria combined, as described in the Methods section. a, b Boxplots of urinary levels of NGAL (a) and EGF (b) measured during the first day of life in newborns with HIE +AKI (HIE–AKI; n = 10), with HIE but without AKI (HIE–non AKI; n =15), and healthy term newborns (Controls; n = 27). *p values were estimated by ANOVA according to the Kruskal–Wallis test, followed by Dunn’s multiple comparisons test. a Significance: **Control group vs. HIE-non AKI group, p < 005; Control group vs. HIE–AKI group, p < 0.05; *HIE–non AKI group vs. HIE–AKI group, p > 0.05. b Significance **Control group vs. HIE–AKI group, p < 0.05; control group vs. HIE–non AKI group, p > 0.05; *HIE–non AKI group vs. HIE–AKI group, p > 0.05. c ROC curves generated for EGF, NGAL, and EGF + sCr combined, in HIE newborns with and without AKI (n = 25). The AUC for NGAL, EGF, and EGF + SCr is also shown in c. p values for all pairwise AUCs comparisons were > 0.05. The dashed reference line represents a ROC curve for a test with not discriminatory ability. EGF cutoff values and their sensitivity/specificity are given in Table 4.