Estimation of Sex- and Age-Specific Reference Values for Serum Creatinine Using Three Indirect Methods in a Multicenter Setting

BACKGROUND: We estimate age- and sex-specific reference intervals (RIs) for serum creatinine using indirect methods across multiple Romanian laboratories and evaluate their clinical relevance compared to manufacturer-provided RIs. METHODS: Data were collected retrospectively from 6 laboratories representing a diverse patient population. Three indirect statistical independent methods, RefLim, the TML (truncated maximum likelihood), and refineR were applied. Data were preprocessed to exclude repeated measurements and high-risk patient samples. Results were stratified by age, sex, and clinical setting (outpatients vs inpatients). RESULTS: Clear age-related patterns were identified, with females showing a steady increase in creatinine and males a more complex pattern. In most female groups, the upper reference limits derived from indirect methods were 15% to 20% below manufacturer-provided RIs. Creatinine medians were 0.60 to 0.66 mg/dL (53.05 to 58.36 µmol/L) in women and 0.85 to 0.92 mg/dL (75.16 to 81.35 µmol/L) in men, diverging from European Kidney Function Consortium (EKFC) equation Q values. CONCLUSIONS: The use of indirect methods to establish RIs may capture population-specific differences that are not fully reflected by manufacturer-provided intervals. However, their results depend on rigorous preprocessing. Our results highlight that, while overall agreement exists among the TML and refineR approaches, careful consideration is needed for older patient groups where variability is higher. Ultimately, integrating locally derived RIs into clinical practice may improve patient care.