Tamara van Donge

Chapter 9 170 suboptimal KI biomarker performance could be that prior research in neonates, infants and children has rarely accounted for developmental (physiological) changes when interpreting KI biomarker levels. These results highlight the influence of maturation and development on renal physiology as well as the importance of original research and validation studies in children. 2 Characterizing reference ranges and “controls” in pediatrics When investigating new KI biomarkers for the monitoring of kidney function and early detection of KI, it is of importance to first determine reference or normative values of these markers in the healthy pediatric population. One prerequisite is that the investigated pediatric population should be marked as healthy, and have no kidney diseases such as, for example, glomerulonephritis, amyloidosis, acute kidney injury, or lupus nephritis, and in addition, no other renal dysfunction. Furthermore, the so-called healthy study participants should not suffer from other disorders, which can influence kidney function (e.g. chronic inflammatory diseases, urinary tract infections, hypertension, dehydration, shock, or diabetes mellitus), and should not be under treatment with potential nephrotoxic drugs, such as aminoglycosides, cyclosporine, JAK-inhibitors, nonsteroidal anti-inflammatory drugs or chemotherapeutics (e.g. ifosfamide/cisplatin or carboplatin). A comprehensive approach using age-specific KI biomarkers in healthy pediatric populations to obtain reference values is crucial for the development of validated pediatric KI biomarkers, and will improve the outcomes in pediatric patients with kidney diseases. 2 Although few papers report reference values of various KI biomarkers assessed in a healthy pediatric population, many perform a comparison of KI biomarker values between pediatric patients with kidney diseases, critical ill pediatric patients and control subgroups. 18-20,27-34 A majority of studies did investigate KI biomarker values in pediatric patients with severe clinical conditions such as acute kidney injury, and are compared with controls , patients who did not developed acute kidney injury. However, as the concentrations of these studied biomarkers in acute kidney injury patients are significantly increased compared to the controls, they might as well be elevated in the control group compared to a healthy pediatric group, since a lack of acute kidney injury does not necessarily imply a lack of other conditions which can influence the kidney function. 18 For this reason, these disease controls cannot be denoted as true controls for establishing a reference or normative range. Consequently, we will focus on reference values for kidney biomarkers in the healthy pediatric population. Moreover, extra attention needs to be given to a very special pediatric population, the preterm neonate. Nowadays these neonates, born after 22-37 weeks of gestation, are treated in neonatal intensive care units across the globe. The majority of these neonates