Proenkephalin as a new biomarker for pediatric acute kidney injury – reference values and performance in children under one year of age

Stan J F Hartman,Dick Tibboel,Remi Beunders,Joost Van Rosmalen,Peter Pickkers,Michiel F Schreuder,Alexandra J M Zwiers,Janin Schulte,Saskia N De Wildt,Joachim Struck,Oliver Hartmann,Nadies E C Van De Water

doi:10.1515/cclm-2020-0381

Abstract

Objectives Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119-159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1year. Methods Observational cohort study in healthy infants and critically ill children aged 0-1years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and β-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis. Results PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9pmol/L, Stage 2 704.0pmol/L, Stage 3 930.5pmol/L) than non-AKI patients (n=51, 432.2pmol/L) (p<0.001). PENK appeared to relate better to AKI diagnosis than CysC and BTP (AUROC PENK 0.858, CysC 0.770 and BTP 0.711) in the first 24h after recruitment. Conclusions PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker.

Highlights

Acute kidney injury (AKI) is common in hospitalized children, with a prevalence in the pediatric ward and pediatric intensive care unit (PICU) ranging from 5 to 51% [1, 2]
[32] were excluded because insufficient serum was available for Proenkephalin A 119–159 (PENK) measurement or serum creatinine concentration (SCr) z-scores were outside the predefined range
The availability of age-related reference values is crucial for the clinical implementation of biomarkers in children, as ignoring age-dependent changes in normal values may lead to inaccurate performance in children [30]

Summary

Introduction

Acute kidney injury (AKI) is common in hospitalized children, with a prevalence in the pediatric ward and pediatric intensive care unit (PICU) ranging from 5 to 51% [1, 2]. AKI causes an accumulation of possibly toxic solutes, including renally excreted drugs, and is independently associated with morbidity and mortality [3, 4]. AKI detection can drive clinicians to alter the dose or dose interval to prevent drug-induced organ toxicity. A conservative fluid management strategy can be applied to prevent fluid overload, which is associated with mortality [5]. While the search for accurate AKI biomarkers has seen promising candidates, they all have important limitations. This work is licensed under the Creative Commons Attribution 4.0

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