Tamara van Donge

Reference intervals for kidney biomarkers in pediatrics 195 10 Introduction Early detection of (drug-related) glomerular and tubular kidney injury in infants, children and adolescents is crucial for clinical monitoring and therapeutic decision-making. Currently, there is a lack of validated diagnostic approaches to detect early (drug- related) kidney injury in pediatric patients. This can result in adverse long-term kidney function outcomes, particularly in patients treated with potential nephrotoxic drugs (e.g. chemotherapy or antibacterial drugs). Simple extrapolation of kidney function and injury markers, often established in adults, to pediatric populations have the limitation that (i) adult and pediatric kidney diseases are different and, more importantly, (ii) maturational and physiological changes cannot be neglected. 1 Therefore, it is important to account for developmental changes when interpreting kidney function and injury marker concentrations in the pediatric population. Serum creatinine (SCR) and (estimated) glomerular filtration rate (GFR) are commonly used clinically to evaluate kidney function, although these are not ideal markers for early detection and monitoring renal and particularly tubular injury in pediatrics. 2,3 The most accurate assessment of GFR using inulin or iohexol is cumbersome, invasive and not suitable for regular monitoring of kidney function. 4 This is particularly true for the pediatric population. For this reason, estimations of GFR by applying calculations relying on endogenous markers (e.g. SCR) are commonly used. Such endogenous markers are thought to imitate the exogenous markers as closely as possible. The (updated bedside) Schwartz formula estimates kidney function based on the children’s height and SCR. 5,6 Despite the standardization of creatinine assays, the estimated GFR (eGFR) has considerable imprecision due to non-GFR related variation of SCR, e.g. rise in SCR levels after meat consumption. 7 Furthermore, disease related muscle mass variations and nutritional changes can result in overestimation of eGFR leading to potential overdosing of nephrotoxic drugs. 8 Investigations of alternative kidney function and injury markers have been the subject of increased interest over the last decades, especially for the pediatric population. 2 Most low molecular weight proteins, such as beta 2-microglobulin (B2M), beta-trace protein (BTP), neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CYSC), are filtered by the glomerulus and reabsorbed by the proximal tubules (Table 1). While increased serum concentrations of these markers indicate glomerular damage, an increase in urinary concentrations implies tubular injury. 3,9 Uromodulin (URO) is a glycoprotein, which is exclusively produced by the cells in the thick ascending limb, and lower serum levels indicate a function decrease of these epithelial cells. 10,11 It has been demonstrated that urinary NGAL, urinary kidney injury molecule-1 (KIM-1) and serum CYSC show a decreasing trend from preterm neonates to infants. 2,12-20