Tamara van Donge

Kidney injury biomarkers in pediatrics 183 9 currently used clinical kidney parameters often are not useful, particularly for early detection of tubular damage. Therefore, there is a clear need for better evaluation of KI biomarkers that permit early detection and localization of KI in neonates, infants and children. Only with early detection severe acute or chronic kidney disease may be recognized and prevented. Various biomarkers are specific for particular locations in the kidney (e.g. tubule or glomerulus) (Table 1). During the last decade, the U.S. Food and Drug Administration has provided a list of qualified renal biomarkers for the assessment of nephrotoxicity (in clinical trials). Although numerous biomarkers (e.g. KIM-1, albumin, beta-2 microglobulin, cystatin C, etc.) have been shown to provide additional and complementary information to serum creatinine, most of these tests are performed in male rats or healthy adult volunteers. This Biomarker Qualification Process, which is a formal framework to obtain regulatory advice from the Center for Drug Evaluation and Research on assessing the suitability of a biomarker, can be applied to drug development in special populations as well, such as pediatrics. Care needs to be taken that biomarker values established in the adult population are not simply extrapolated to the pediatric population, neglecting maturational and physiological changes. In addition, despite the fact that considerable human data exist for some of these biomarkers, they are not yet qualified for routine monitoring of drug-induced nephrotoxicity in the clinical setting. 48-51 The next step should be to obtain reference values in healthy pediatric populations, both in urine and serum, for different age groups, in order to subsequently compare them with pediatric patients with KI. Moreover, it seems that in the not so distant future, conventional markers may be exchanged for novel ones; however, the confirmation of their efficacy, sensitivity and specificity, as well as the reduction in analysis costs is required. Collecting data in (healthy) pediatric populations is subject to abundant ethical constraints. An example of setting up such a clinical trial could be to investigate new KI biomarkers in healthy infants and children undergoing elective surgery such as tonsillectomy or circumcision. As for these medical interventions anesthesia is required, which is often given by a venous line and allows for painless blood sampling. Overall, there has been little focus on conducting KI biomarker research specifically in children for developing age-adjusted reference ranges. When accounting for age in drug dosing recommendations and using age-based cut-off values for clinical test, why do we not account for age in KI biomarker reference values? The comparison of reference ranges collected from pediatric populations to adult reference values does not represent a transparent and appropriate approach, and should not be performed because of the age-related physiological changes. Future research should focus on, and account for, developmental (physiological) changes (especially age) when assessing and interpreting KI biomarker levels.