Tamara van Donge

Kidney injury biomarkers in pediatrics 181 9 Discussion In total 12 studies analyzed KI biomarkers in healthy pediatric population. Values of key KI biomarkers such as urinary NGAL, urinary KIM-1 and serum cystatin C appear to decrease from prematurity to infancy. In total, 26 KI biomarkers are mentioned of which only three biomarkers (urinary KIM-1, urinary NGAL, serum cystatin C) were analyzed in multiple studies. Particularly KI biomarkers such as urinary NGAL, urinary KIM-1, serum cystatin C, beta-trace protein, and beta-2 microglobulin seem to be of interest in pediatrics. What do we know about reference ranges in pediatrics? In the last decade, research on KI biomarkers has increased immensely. 2 Although many of these biomarkers are highly sensitive and selective, and have shown promising results, few of them have been validated or implemented in pediatric clinical settings. 1,40 For kidney disease progression in adults, it has been demonstrated that the combination of creatinine, serum cystatin C and urine albumin to creatinine ratio can improve the risk stratification. 40 Another study performed in a healthy adult population showed that higher concentrations of urinary NGAL could be used as an early indicator for patients at risk for renal tubular damage. 41 In addition, it has been investigated that urinary NGAL is a more specific biomarker for the prediction of acute kidney injury in adults as compared with urinary interleukin-18. 42 Unfortunately, the situation for the pediatric population is not so straightforward. These insights from the adult population cannot be simply extrapolated to infants and children; first, creatinine is an inaccurate marker for KI in pediatrics and, second, maturation and developmental changes have an effect on the KI biomarker values. As illustrated, even in the pediatric population, the reference values for NGAL vary between different age groups (Figure 2 and 3). As we are using age-based cut-off values for clinical tests and drug dosing in infants and children, we should also be using them for KI biomarker (reference) values. As pointed out in Table 2, only one study analyzed KI biomarkers in both urine and serum. 43 The majority of studies investigated biomarkers in either urine or serum. Therefore, the ratio between the same KI biomarker measured in urine and serum remains unknown. Sample collection in pediatric populations is more difficult compared to adults, since drawing blood is often linked with fear and pain, and specifically in preterm neonates only a limited number of samples can be obtained due to the risk of anemia. Urine sampling might be less invasive, although this approach in (preterm) neonates and infants can be cumbersome as well. New urinary KI biomarkers are often normalized to urinary creatinine. 19,44,45 This normalization is performed to circumvent the problem that the urinary concentration of the biomarker (variability of water content) may change