BackgroundResearch on acute kidney injury (AKI) has focused on identifying early biomarkers. However, whether AKI could be diagnosed in the absence of the classic signs of clinical AKI and whether the condition of subclinical AKI, identified by damage or functional biomarkers in the absence of oliguria or increased serum creatinine (sCr) levels, is clinically significant remains to be elucidated in critically ill children. The aims of the study were to investigate the associations between urinary cystatin C (uCysC) levels and AKI and mortality and to determine whether uCysC-positive subclinical AKI is associated with adverse outcomes in critically ill neonates and children.MethodsIn this prospective cohort study, uCysC levels were serially measured during the first week after intensive care unit (ICU) admission in a heterogeneous group of patients (n = 510) presenting to a tertiary neonatal and pediatric ICU. The diagnosis of neonatal AKI that developed during the first week after admission was based on neonatal KDIGO criteria or sCr >1.5 mg/dL, and pediatric AKI was based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The term “uCysC(−)” or “uCysC(+)”, indicating the absence or presence of tubular injury, was defined by the optimal peak uCysC cutoff value for predicting ICU mortality.ResultsThe initial and peak uCysC levels were significantly associated with AKI and mortality, and had an area under the receiver operating characteristic curve of 0.76 and 0.81, respectively, for predicting mortality. At the optimal cutoff value of 1260 ng/mg uCr, the peak uCysC displayed sensitivity of 79.2% and specificity of 72.3% for predicting mortality. Among all patients, 130 (25.5%) developed uCysC(+)/AKI(−) status during the first week after admission. The adjusted odds ratio for patients with uCysC(+)/AKI(−) status in association with an increased risk of mortality compared with that for patients with uCysC(−)/AKI(−) was 9.34 (P < 0.001). Patients with uCysC(+)/AKI(−) spent 2.8 times as long in the ICU as those with uCysC(−)/AKI(−) (P < 0.001).ConclusionsBoth initial and peak uCysC levels are associated with AKI and mortality and are independently predictive of mortality in critically ill neonates and children. Subclinical AKI may occur without detectable loss of kidney function, and uCysC-positive subclinical AKI is associated with worse clinical outcomes in this population.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2193-8) contains supplementary material, which is available to authorized users.

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Background: Nephrin is a key component of the slit diaphragm of the glomerular podocyte, and increased urinary nephrin level may reflect glomerular injury. Objectives: To determine whether urinary nephrin is a useful biomarker of glomerular maturation and injury and whether it is associated with acute kidney injury (AKI) and neonatal intensive care unit (NICU) mortality in critically ill neonates. Methods: Urinary samples were serially collected in 234 neonates during NICU stay for measurements of nephrin, cystatin C (CysC), and albumin. AKI diagnosis was based on neonatal Kidney Disease: Improving Global Outcome (KDIGO) criteria. Results: Of the neonates, 26 developed AKI and 24 died during NICU stay. The independent contributors to the initial urinary nephrin level obtained on the first 24 h admitted to NICU were gestational age (p = 0.004) and initial urinary CysC level (p < 0.001). Both initial (p = 0.037) and peak (p = 0.039) urinary nephrin were significantly associated with AKI, even after controlling for significant covariates, and had an area under the receiver-operating characteristic curve (AUC) of 0.71 and 0.70, respectively, for predicting AKI. At the optimal cutoff value of 0.375 μg/mg urinary creatinine, the initial urinary nephrin displayed sensitivity of 61.5% and specificity of 76.9% for predicting AKI. The AUCs for initial and peak urinary nephrin to predict NICU mortality were 0.81 and 0.83, respectively. Conclusions: Urinary nephrin, which may decrease with increasing glomerular maturity, is significantly associated with increased risk for AKI and NICU mortality even after adjustment for potential confounders. A higher level of urinary nephrin may be independently predictive of AKI and NICU mortality in critically ill neonates.