Preliminary reference intervals for cystatin C and beta-trace protein in preterm and term neonates☆
Introduction
Renal function is routinely monitored in the neonate to ensure safe dosing of medication, and to assess hydration status and renal effects of various pathologies [1]. Glomerular filtration rate (GFR) is the most reliable indicator of kidney function and kidney disease progression [2]. The reference methods for determining GFR in children include inulin clearance and nuclear medicine methods (99mTc DTPA, 51Cr-EDTA, etc.), which are expensive, invasive, may involve radiation, and are time consuming. As a result, GFR is estimated based on endogenous surrogate markers such as creatinine, or small molecular weight proteins such as cystatin C (CysC) and beta-trace protein (BTP) [3]. CysC is a cysteine proteinase inhibitor with a molecular mass of 13 kDa that is expressed in all nucleated cells, is produced at a constant rate and is solely cleared by the kidneys [4]. A meta-analysis indicates that CysC is superior to serum creatinine (Cr) for the detection of impaired GFR [5]. BTP, also known as prostaglandin D synthase, is a low molecular weight protein (a 23- to 29-kDa enzyme) that has been traditionally used as a marker for cerebrospinal fluid leakage [6], [7]. BTP is another promising surrogate marker for the GFR measurement [8], [9]. Like CysC, it is freely filtered by the glomerulus and its serum concentration depends on the GFR. Previous studies have confirmed a good correlation between serum BTP levels and the GFR measurement by nuclear medicine methods [10].
In children, variability of muscle mass, age, gender, diet, amount of creatinine filtered by the glomerulus, proximal tubule secretion, tubular reabsorption, and gastrointestinal elimination renders Cr problematic as a tool for GFR assessment [11]. Moreover, in neonates, serum creatinine reflects largely the maternal creatinine [12]. During gestation, GFR remains constant, but 24 h after delivery, the GFR increases three-fold, continues to increase slowly thereafter, and reaches steady state at 18 months [13]. Neonatal creatinine reflects maternal values even up to 72 h post-delivery [14]. By contrast, CysC and BTP do not cross the placenta [15] and should therefore truly reflect neonatal kidney function. Neonatal reference intervals for CysC remain sparse, whereas no BTP reference intervals exist in preterm neonates.
Section snippets
Methods
The ethics board of The Ottawa Hospital, General Campus approved the study and informed consent was obtained from each infant's parents. A two-year study was conducted on a convenience sample of infants, ranging from 24 weeks gestation to full term, admitted to a tertiary neonatal intensive care unit from December 2004 to January 2007. Infants were excluded if they were born to mothers with a serum creatinine > 90 μmol/L, or a history of renal disease, diabetes, hypertension, pre-eclampsia, or
Results
The study included 128 neonates (46 female, 36%) with median gestational age of 32.4 weeks (inter-quartile range 29.2, 34.9). The study included 92 singletons, 24 twins and 12 triplets.
Results indicated no significant gender differences for all surrogate GFR markers (data not shown); therefore, data from both genders were combined. Table 1 summarizes the reference intervals for each gestational age group. To acknowledge the small sample size in each group, we also calculated the more stringent
Discussion
Only a few studies expressing the reference intervals of CysC exist in preterm and term neonates [16], [17], [18], and there are none for BTP. Median CysC values on days 1 and 3 of life for infants of all gestational ages in our study were similar to the mean values on days 1 and 3 reported in a recently published study that assessed 108 preterm infants [18]. Our CysC values on day 1, however, were lower than the mean values reported by Harmoinen et al. [17]. This discrepancy could be due to
Conclusion
This study is the first to determine reference values for BTP in preterm and term neonates. It also suggests that BTP, similar to CysC, is a promising neonatal renal marker that is independent of gestational age.
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Support/funding for the study: this study was supported by a Feasibility/Start-up Grant of $30,000 from the CHEO Research Institute awarded to EB and GF.