Tamara van Donge

Reference intervals for kidney biomarkers in pediatrics 209 10 (ibuprofen, isotretinoin) potentially associated with renal side effects. Ibuprofen was discontinued the day before surgery, and as the half-life of ibuprofen is approximately two hours, near complete elimination of ibuprofen can be assumed after 8-10 hours. 28 SCR concentrations were comparable with previous published reference values for healthy pediatric populations. 24,25 The calculated median SCR values according to the reported age groups did not differ by more than 20% (8% on average) with the 2.5% and 97.5% percentiles from data presented in previous studies (Table S7). 24,25 Our study population represents a healthy pediatric population, as we have applied strict inclusion and exclusion criteria. This is in contrast to previous studies, where subgroups of a diseased patient group serve as controls and do not guarantee the absence of other conditions influencing kidney function. Establishing reference intervals of kidney function and injury markers in a healthy pediatric population is a necessary component for demonstrating the clinical utility of these markers and will allow their interpretation in ill pediatric patients. Furthermore, the use of several markers in addition to SCR, ALB and eGFR in clinical routine will support the interpretation of physiological and pathological conditions. Beta 2-microglobulin (B2M) concentrations appeared to be higher for infants (1.9 mg/L [1.3-2.5]) and remain constant in children and adolescents. B2M concentrations are strongly associated with cell turnover, which is a physiological state in early infancy, as well as various infectious and hematological diseases. 3,22 During infectious diseases an increase in B2M concentrations is observed. 29,30 Beta-trace protein (BTP) shows a similar profile with highest concentrations in infants (0.9 mg/L [0.6-1.1]). Serum BTP is a small molecular weight protein which is freely filtered through the glomerulus. It has been previously shown that serum BTP concentrations in pediatric patients with impaired kidney function (eGFR < 90 mL/min/1.73m 2 ) are decreased (mean of 0.68 mg/L). 31 In this study, a small, although statistically significant, positive relationship between albumin (ALB) concentrations and age has been observed. This ALB increase with age has also been illustrated by several other studies. 32,33 Clinical significance of this age-dependency is unclear, given that the 95% predicted reference intervals of ALB for our cohort were similar across all age groups. Our results confirmed the age-dependence of serum creatinine (SCR) concentrations. 24,25 After the first couple of months of life, SCR concentrations increase as a result of increasing muscle mass. Kidney injury molecule-1 (KIM-1) is removed from tubular epithelial cells into the urine in response to injury; therefore, an increase in urinary KIM-1 concentrations could indicate kidney damage. 34 In this study, a small, although statistically significant, negative association of KIM-1 with age was detected. Urinary KIM-1 concentrations in healthy pediatric populations has been shown to increase with age (3.8%/year), although up to now, no published data could be found for serum KIM-1 concentrations in healthy pediatric population. This study showed that cystatin C (CYSC) concentrations decrease until the age of approximately 2 years is reached, after which CYSC concentrations showed an