Tamara van Donge

Abstract Background: The use of kidney function and injury markers for early detection of drug- related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin, beta 2-microglobulin, beta-trace protein, creatinine, cystatin C, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, uromodulin) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). Results: Albumin and creatinine increased with age (p<0.01), whereas beta 2-microglobulin, beta-trace protein and kidney injury molecule-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. Cystatin C showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. Neutrophil gelatinase-associated lipocalin and uromodulin did not show any age-dependency. Conclusion: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence. Keywords : kidney biomarker, age-dependency, reference intervals, pediatrics, kidney injury List of Abbreviations: Glomerular filtration rate (GFR), creatinine (SCR), estimated GFR (eGFR), beta 2-microglobulin (B2M), beta-trace protein (BTP), neutrophil gelatinase- associated lipocalin (NGAL), cystatin C (CYSC), uromodulin (URO), kidney injury molecule-1 (KIM-1), ALB (albumin), standard deviation (SD), interquartile range (IQR), confidence interval (CI), Clinical and Laboratory Standards Institute (CLSI)