Are cystatin C and beta 2-microglobulin better markers than serum creatinine for prediction of a normal glomerular filtration rate in pediatric subjects?

Serum creatinine is the marker most widely used to predict glomerular filtration rate (GFR). In childhood, there is age and muscle mass dependency of serum creatinine, and assessing a normal GFR accurately even with the use of body length/creatinine ratios remains difficult [1, 2]. Recently, cystatin C (Cys-C), a 13-kDa protein, was found to correlate closely with GFR in adults [3–5]. b2-Microglobulin (b2-MG) serum concentrations also correlate with GFR, and have been shown to be age independent in infants [6]. Here, we report reference limits of Cys-C and b2-MG in children between ages 0.8 and 18 years and demonstrate age independency of these parameters as an essential advantage compared with the conventionally used serum creatinine values. We studied serum Cys-C and b2-MG in 216 urological pediatric patients (age range 0.8 to 18 years, mean 11.0 6 6.2 years) with normal GFR, using leftover serum after routine serum chemistry measurements, including serum creatinine. The study is in accordance with the ethical standards of the Helsinki declaration of 1975 (revised in 1983), and parents’ (in the case of 18-year-olds: patients) oral consent was obtained in each case. Cr–EDTA clearance studies with a modified method of Chantler and Barratt [7] served as a gold standard for GFR assessment; values between 90 and 150 mL/min per 1.73 m were defined as normal GFR. Cys-C was measured with the particle-enhanced turbidimetric assay (Dako, Glostrup, Denmark) in the Hitachi 717 analyzer. b2-MG was measured with the microparticle enzyme immunoassay (Abbott, Wiesbaden, Germany), and serum creatinine was determined enzymatically (PAP; Boehringer Mannheim, Mannheim, Germany). We calculated correlation coefficients according to Spearman and regression coefficients between age and serum concentrations of creatinine, Cys-C, and b2-MG, and a strong correlation between creatinine concentration and age could be demonstrated (Fig. 1). Cys-C and b2-MG showed slopes of the regression lines not significantly different from zero and there was no correlation between their concentrations and age. Thus, age-independent reference values for both low-molecular-mass proteins can be considered. We calculated the central 95% reference intervals according to the IFCC guidelines by using the nonparametric method [8]. The upper 97.5 percentiles amounted to 1.38 mg/L for Cys-C and 2.27 mg/L for b2-MG. Likewise, the lower 2.5 percentiles amounted to 0.18 mg/L for Cys-C and 0.361 mg/L for b2-MG. Those data correspond to values found in adults [4, 5]. In subjects with normal GFR (.80 mL/min per 1.73 m), a preliminary reference interval between 0.61 and 1.21 mg/L was defined [4]. Newman et al. [5] used 1.25 mg/L as the upper reference value. However, all these references values were established in a very limited number of subjects (n 5 27) [4]. Using an ELISA method, we previously found higher values [3]. These differences are very likely explained by Fig. 1. Relation between age and serum concentrations of creatinine, Cys-C, and b2-MG in children.