Reference ranges for plasma cystatin C and
creatinine measurements in premature infants,
neonates, and older children
H Finney, D J Newman, H Thakkar, JMEFell, C P Price
Abstract
Aim—To establish a reference range in the
paediatric population for the new
glomerular filtration rate (GFR) marker,
cystatin C, and to compare it with that of
creatinine.
Methods—Cystatin C and creatinine were
measured by particle enhanced nephelo-
metric immunoassay (PENIA) and fixed
interval JaVé methods, respectively, in 291
children aged 1 day to 17 years, including
30 premature infants with gestational ages
ranging from 24 to 36 weeks.
Results—In the premature infants, con-
centrations of both cystatin C and creati-
nine were significantly raised compared
with term inf ants, with cystatin C concen-
trations being between 1.10 and 2.06 mg/
litre and creatinine between 32 and
135 µmol/litre. In premature infants, there
was no significant relation between
gestational age and cystatin C or creati-
nine concentration. Creatinine concentra-
tions fell to a nadir at 4 months of age,
rising gradually to adult values by about
15–17 years of age, in contrast to cystatin
C, which fell to a mean concentration of
0.80 mg/litre by the 1st year of life, and
remained constant throughout adulthood
up to the age of 50 years. Neither analyte
showed any influence of sex.
Conclusion—The measurement of cysta-
tin C, rather than creatinine, is more
practical for monitoring GFR changes in
the paediatric population.
(Arch Dis Child 2000;82:71–75)
Keywords: reference ranges; glomerular filtration rate;
cystatin C; creatinine
The measurement of the glomerular filtration
rate (GFR) is an important part of the clinical
evaluation of renal function.
12
Although the
measurement of serum creatinine concentra-
tions is the most common method for estimat-
ing GFR, it often fails to identify those patients
with moderately reduced renal function. The
investigation of renal function in children is
complicated by the superimposition of con-
tinuing renal development overlaying any pos-
sible renal damage. Furthermore, the changing
muscle mass of the infant influences the circu-
lating creatinine concentration, and the analyti-
cal interferences of bilirubin and haemoglobin
are important in this population, because of the
problems of neonatal jaundice and the in vitro
haemolysis that occurs with the collection of
small paediatric samples.
2
Thus, it would be an
advantage if an alternative marker of GFR were
available that was unaVected by changing mus-
cle mass, which could be measured by a
technique that was free from these analytical
problems.
Cystatin C, a 13 600 Da cysteine protease
inhibitor constitutively synthesised by all nu-
cleated cells, has been shown by ourselves and
others to be a more specific and sensitive
marker of GFR in adults.
3–5
Fully automated
immunoassays for cystatin C are now available
using the same analysers that are used for cre-
atinine measurement.
6–8
These immunoassays
are free from bilirubin, ketone, and haemo-
globin interference and need only a few micro-
litres of serum or plasma. Furthermore, in
adult studies, the serum concentration of
cystatin C shows no relation to muscle mass
and is not aVected by inflammatory stimuli.
34
Although cystatin C concentrations in children
are poorly described, it seemed likely that
measurement of cystatin C might provide a
considerable improvement over creatinine
measurement as a marker for changes in GFR.
Although there is a range of algorithms
available for the calculation of predicted creati-
nine clearance for use in children, they are not
suitable for immediate clinical application. A
simple serum or plasma concentration is always
easier to interpret, and the measurement of
cystatin C seems to oVer this benefit.
There are limited data available on reference
ranges for cystatin C. Norlund and colleagues
9
have established an adult reference range,
which we have confirmed recently.
10
An exten-
sion of this study was to establish a paediatric
reference range for which very few data have
been collected,
11–13
and to extend the range to
premature infants and neonates for which no
data have been recorded.
Here, we have set out to establish a paediatric
reference range for cystatin C and for creatinine
including preterm and term neonates.
Materials and methods
CREATININE
We measured serum and plasma creatinine
concentrations using a fixed interval JaVé
method performed on the Monarch 2000
(Instrumentation Laboratory, Warrington,
UK) with reagents supplied by the manufac-
turer. The method was calibrated using
ReferrIL A Calibrator (catalogue number
35261), an aqueous solution for creatinine
calibration, on the Monarch 2000. We used
Nycomed (Oslo, Norway) low, medium, and
Arch Dis Child 2000;82:71–75 71
Department of Clinical
Biochemistry, St
Bartholomew’s and
The Royal London,
School of Medicine
and Dentistry, Turner
Street, London E1
2AD, UK
H Finney
CPPrice
South West Thames
Institute for Renal
Research, St Helier
NHS Trust, Wrythe
Lane, Carshalton,
Surrey SM5 1AA, UK
D J Newman
Clinical Pathology,
SmithKline Beecham
Pharmaceuticals, The
Frythe, Welwyn,
Hertfordshire AL6
9AR, UK
H Thakkar
Department of
Paediatric
Gastroenterology,
Chelsea and
Westminster Hospital,
369 Fulham Road,
London SW10 9NH,
UK
JMEFell
Correspondence to:
Ms Finney
email: h.finney@
mds.qmw.ac.uk
Accepted 14 September 1999
high control materials for quality control. We
obtained published age related reference
ranges for creatinine via a literature search.
14–24
CYSTATIN C
We measured serum and plasma cystatin C
concentrations using latex particle enhanced
immunoassays; for the term neonates and the
remaining children’s samples we performed the
assay on the BNA (Behring Nephelometer
Analyser; Dade Behring Marburg GmbH,
Marburg, Germany).
8
However, for the prema-
ture infants, we used an in house assay
validated as described previously
7
because
these samples were analysed before the BNA
assay became available. The results of the in
house assay have been shown to be directly
comparable to the Dade Behring method.
8
We
calibrated both methods using a standard sup-
plied by Dade Behring, made with purified
cystatin C from human urine, and the value
assigned by amino acid analysis. We used
lyophilised cystatin C control sera from Dade
Behring as the quality control material.
PATIENTS
Paediatric serum samples were collected from
the routine biochemistry laboratory of the
Royal London Hospital after the requested
tests had been completed. All samples had
been refrigerated by the laboratory within six
hours of being collected. Upon collection for
this study, all samples were immediately
aliquoted into 1.5 ml polypropylene tubes and
frozen to −70°C. The criteria for collecting the
samples were that the patients were below the
age of 19 years, that their electrolytes and renal
function test results (creatinine and urea) were
normal, and that they were in hospital because
of an accident or minor surgery. Plasma
samples, which were collected daily and stored
at 4°C before being sent, were also received
from the Birmingham Children’s Hospital and
immediately frozen upon receipt. Altogether
244 patient samples were collected; there were
112 female patients and 132 male patients,
with ages ranging from 2 days to 17 years.
A further 47 plasma samples were collected
from newborn infants who were in the neona-
tal unit or postnatal wards at the Royal London
Hospital. Seventeen of these infants were 7
days old having been born at term. Thirty
babies were 1 day old premature infants, 16
had been born at 24–28 weeks’ gestation, and
14 at 29–36 weeks’ gestation. Most infants
born at 24–28 weeks’ gestation required venti-
latory support, but were otherwise healthy.
None was asphyxiated at birth, defined as an
Apgar < 5 at five minutes or a cord pH < 7.2
at delivery, or had received nephrotoxic medi-
cation, and none was known clinically to have a
specific renal abnormality. The gestational age
was calculated from the first day of the
mother’s last period, confirmed by ultrasound
scans. Our study was approved by the ethics
committee of the Royal London Hospital
Trust. In total, there were 291 patient samples
collected for our study.
STATISTICAL ANALYSIS
We performed all statistical analyses using the
“Astute” statistical package (Diagnostic Devel-
opment Unit, University of Leeds, UK). We
performed tests of normality by means of the
Kolmogorov-Smirnov and Anderson Darling
tests, taking p < 0.05 as a significant result.
The Mann-Whitney U test was used, with
p < 0.05 taken as a significant result.
Reference intervals
The reference intervals for cystatin C were cal-
culated using the mean (2 SD) of the log trans-
formed data and for creatinine by using the
95th centiles of the untransformed data.
Figure 1 Box plot distributions showing (A) cystatin C and (B) creatinine values (10th,
25th, 50th, 75th, and 90th centiles) across the age groups. The categories of 24–28 and
29–36 weeks refer to the gestational ages of preterm babies. Dotted lines indicate 95%
confidence interval of adult range.
10
Preterm babies born between 24–36 weeks’ gestation
were 1 day old when samples were taken.
180
140
160
100
120
80
40
60
20
0
Age
Creatinine (µmol/l)
24–28 weeks
29–36 weeks
0–3 months
4–11 months
1–3 years
4–8 years
9–17 years
Adult
n = 16
n = 14
n = 46
n = 29
n = 53
n = 70
n = 59
n = 309
3.00
B
A
2.50
2.75
2.00
2.25
1.75
1.25
1.50
1.00
0.75
0.25
0.50
Cystatin C (mg/l)
24–28 weeks
29–36 weeks
0–3 months
4–11 months
1–3 years
4–8 years
9–17 years
Adult
n = 16
n = 14
n = 50
n = 29
n = 53
n = 70
n = 59
n = 309
72 Finney, Newman, Thakkar, Fell, Price
Results
The between batch coeYcient of variation
(n = 10) of the quality controls (QC) for each
method were as follows: JaVé creatinine (µmol/
litre): low QC, 10.1% (mean, 50.1; SD, 5.3);
medium QC, 1.3% (mean, 196.9; SD, 2.6);
and high QC, 1.3% (mean, 485.1; SD, 6.1);
PENIA cystatin C (mg/litre): QC, 2.6% (mean,
1.28; SD, 0.034).
The frequency distributions for cystatin C
and creatinine were both non-Gaussian, even
when separated by sex. Only cystatin C values
reverted to a Gaussian distribution after log
transformation. Neither of the analytes showed
any significant sex diVerences using the Mann-
Whitney U test. Figure 1 shows box plot distri-
butions of analyte concentrations across the
age groups. Cystatin C concentrations were
highest in premature and full term neonates,
and gradually declined with increasing age
until about 1 year, when adult values were
reached (fig 1A). Creatinine concentrations
were also highest in the premature and full
term neonates during the 1st week of life, then
dropped to approximately 40 µmol/litre, result-
ing in a very wide variation in values, followed
by a progressive increase to adult concentra-
tions during adolescence (fig 1B). The largest
creatinine increases occurred at 9–17 years of
age with the onset of puberty. Female adult
creatinine values were reached at about 18
years, but male adolescent values were lower
than adult values. Creatinine values for each
age group were all significantly diVerent from
each other (p < 0.0001), except between 4–11
months and 1–3 years, whereas only those
groups below 1 year had significantly higher
(p < 0.0001) cystatin C concentrations.
For the premature babies, the cystatin C
values were less variable than the creatinine
values. Cystatin C values at birth, whether pre-
term or full term, were higher than adult values
and fell over the age of 1–2 months. Table 1
shows the reference intervals for each analyte
for diVerent age groups. For cystatin C, we cal-
culated three ranges: premature infants
(n = 30), 0.43–2.77 mg/litre (mean, 1.56);
over 1 year (n = 79), 0.59–1.97 mg/litre
(mean, 1.20); and 1–17 years (n = 182), 0.50–
1.27 mg/litre (mean, 0.82). For creatinine, we
calculated the following ranges: premature
infants (n = 30), 27–175 µmol/litre (median,
78); younger than 1 year (n =79), 33–
127 µmol/litre (median, 44); and 1–17 years
(n = 182), 35–88 µmol/litre (median, 56).
Discussion
This is one of the first studies to assess kidney
function in premature infants and children
using the new GFR marker, cystatin C.
Although serum creatinine is the most widely
used marker of renal function, it is insensitive
to small changes in renal function and is
proportional to muscle mass and body weight,
which increase with growth. Cystatin C con-
centrations are unaVected by these physiologi-
cal variables and might therefore reflect GFR
more closely in the paediatric population.
We have compared creatinine and cystatin C
values in children and adolescents, ranging
from 24 weeks premature to 17 years of age.
The creatinine concentrations across the age
groups (fig 1B) confirmed the results of others,
with high creatinine values at birth and during
the 1st week of life, which then decreased to
approximately 40 µmol/litre. A study by Feld-
man and Guignard
17
showed that there was a
wide range of creatinine values during the first
5 days of life in infants born at 30–40 weeks.
These high creatinine concentrations at birth,
possibly of maternal origin, declined dramati-
cally during the 1st month of life, greatly
reducing the value of creatinine as an index of
GFR in infants. Creatinine concentrations
remained constant until 2 years of age, at which
point they were seen to rise to adolescent
values, in agreement with the findings of
Schwartz et al.
14
Newborn infants have a
Table 1 Summary of reference range data obtained
Age
All Girls Boys
n Mean/median (range) n Mean/median (range) n Mean/median (range)
Cystatin C (mg/litre)
24–28 weeks* 16 1.48 (0.65–3.37)
29–36 weeks* 14 1.65 (0.62–4.42)
0–3 months 50† 1.37 (0.81–2.32) 14 1.28 (0.73–2.26) 19 1.37 (0.85–2.22)
4–11 months 29 0.98 (0.65–1.49) 12 0.94 (0.64–1.35) 17 1.00 (0.63–1.57)
1–3 years 53 0.79 (0.50–1.25) 27 0.76 (0.47–1.21) 26 0.83 (0.57–1.21)
4–8 years 70 0.80 (0.49–1.29) 32 0.74 (0.49–1.11) 38 0.86 (0.52–1.41)
9–17 years 59 0.82 (0.53–1.29) 27 0.83 (0.49–1.45) 32 0.80 (0.56–1.14)
24–36 weeks* 30 1.56 (0.43–2.77)
< 1 year 79† 1.20 (0.59–1.97) 34 1.17 (0.67–2.05) 38 1.20 (0.69–2.08)
1–17 years 182 0.80 (0.50–1.27) 87 0.77 (0.48–1.24) 95 0.83 (0.54–1.29)
Creatinine (µmol/litre)
24–28 weeks* 16 78 (35–136)
29–36 weeks* 14 75 (27–175)
0–3 months 46† 47 (23–127) 11 47 (36–131) 18 50 (35–111)
4–11 months 29 42 (32–100) 12 40 (32–59) 17 42 (34–100)
1–3 years 53 45 (33–60) 27 43 (17–60) 26 48 (34–63)
4–8 years 70 57 (40–82) 32 54 (38–79) 38 59 (40–83)
9–17 years 59 66 (46–94) 27 69 (46–92) 32 66 (43–111)
24–36 weeks* 30 78 (27–175)
< 1 year 79† 44 (33–127) 30 47 (32–132) 36 45 (34–119)
1–17 years 182 56 (35–88) 87 54 (33–85) 95 58 (35–91)
Cystatin C reference intervals are parametric (mean (2 SD)) after log transformation.
Creatinine reference intervals are non-parametric (median) with 2.5 to 97.5 centile range.
*Gestational age.
†Includes term neonates whose sex was not categorised.
Reference ranges for plasma cystatin C and creatinine 73
muscle mass that is 24% of body weight, and
growth in infancy is not associated with a major
change in the proportion of muscle mass.
25
During childhood, accretion of muscle mass
exceeds the increase in body weight so that by
11 to 13 years, 39% of body weight is muscle,
approaching the value of 43% in male adults.
GFR measurement, by
51
Cr-EDTA clear-
ance, has been shown to reach adult values of
114 ml/min/1.73 m
2
by 18 months, and then to
be constant up to 17 years.
26
This makes the
measurement of serum creatinine unreliable
when its concentration rises continuously
because of an increase in muscle mass. The
cystatin C values in our study (fig 1A) mirror
the reported GFR, falling to within the adult
range by 1 year. Cystatin C is raised preterm
until birth; the maternal contribution of cysta-
tin C is unknown.
It has been shown that GFR increases with
postconceptional age at a rate that accelerates
with maturation.
15 16 27
From 20 weeks of gesta-
tion, kidney weight and body weight have a lin-
ear relation to gestational age and body surface
area.
28
Although there are studies that have
measured the changes of GFR occurring in the
last weeks of gestation the results are not
uniform. A study by Aperia et al,
29
measuring
creatinine clearance, showed that preterm
infants, born before 34 weeks’ gestation, had
significantly lower GFRs than full term infants,
and that this diVerence persisted for up to 3–5
weeks postnatally. During the 1st week of life,
the GFR increased significantly more in full
term than preterm infants. Between 1 and 5
weeks of age the GFR increased at a slower rate
in both sets of infants. Brion and colleagues
30
have also shown that GFR measurement, using
inulin and creatinine clearance, increases with
gestational and postnatal age, whether ex-
pressed as absolute value (for each unit surface
area) or for each kg body weight.
Creatinine concentrations were significantly
diVerent between the premature and term
infants. This could be because of the diVerent
postnatal sampling points: the term samples
were collected at day 2 versus day 1 for the
premature infants.
19
Although there are indica-
tions that creatinine reabsorption is increased
in the preterm kidney,
31
this is likely to be pas-
sive diVusion down a concentration gradient, a
process unlikely to occur with a protein like
cystatin C. Once filtered, cystatin C would
normally be reabsorbed and degraded by the
proximal tubular epithelial cells. In the ne-
onate, the tubular length is less than in the
adult so the proportion reabsorbed is likely to
be much less, but the protein will still be
removed and pass into the urine. The much
smaller and statistically insignificant diVer-
ences between the premature and term cystatin
C concentrations suggests a smaller maternal
contribution to the neonatal circulatory pool.
Although a longer half life of cystatin C in the
circulation might contribute to the sustained
level at day 7 in the term infants, our own
(unpublished, 1995) studies during adult
donor nephrectomies suggest that it is, in fact,
not significantly diVerent to that of creatinine.
There is evidence indicating that the longer
half life of dextrans might be the result of
diVerences in the permeability of the neonatal
glomerulus
32
; however, it is possible that this
could be explained by the reduced GFR that is
also present, rather than permeability diVer-
ences. In previous work, looking at the
glomerular permeability and tubular reabsorp-
tion of proteins in neonates, it was concluded
that there was insuYcient evidence to establish
whether the increase in albumin excretion was
the result of an increase in permeability or a
decrease in tubular reabsorption.
33
However,
our data and that of others suggest that a pro-
tein with the molecular weight of cystatin C is
unlikely to be retained to any great degree by
the neonatal kidney. Whereas in the adult kid-
ney, the passage of cystatin C through the
glomerular barrier is less free than the much
smaller creatinine molecule, it will be closer to
that of creatinine in the neonate because of the
greater overall permeability of the neonatal
barrier.
In summary, we have shown that cystatin C
is a better marker of GFR than creatinine in the
paediatric population because it appears to
mirror what is known about the maturation of
renal function more closely. In premature
infants, cystatin C is significantly raised at all
gestational ages. Cystatin C concentrations in
children reach adult values by the age of 1 year
(range, 0.50–1.27 mg/litre; adult range, 0.51–
0.98); therefore, a separate reference range is
not required. Below the age of 1 year, cystatin
C values are higher, reflecting the immaturity
of the kidneys (< 1 year, 0.59–1.97 mg/litre).
Creatinine does not show these trends and is
influenced mainly by the increase in muscle
mass during growth. At birth, the kidneys are
immature and cystatin C concentration
changes suggest it takes 12 months to attain
maturity (in accord with reference GFR meas-
urements), whereas serum creatinine concen-
trations are influenced by increasing muscle
mass and do not reach adult values until after
puberty. Cystatin C concentrations are eVec-
tively constant from 1 year of age upwards.
This suggests that cystatin C might oVer a
considerable advantage to paediatric nephrolo-
gists in the measurement of GFR.
HF was supported by a grant from Dade Behring Marburg
GmbH, Marburg, Germany. We are grateful to colleagues at the
Birmingham Children’s Hospital for collection of some of the
paediatric samples.
1 Chantler C. The measurement of renal function in children:
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Key messages
+ Cystatin C is a better marker than creati-
nine of glomerular filtration rate (GFR)
in preterm infants
+ A single reference range for plasma
cystatin C can be used, regardless of sex,
from 1 year of age
+ Cystatin C oVers a more specific and
practical measure for monitoring GFR in
the paediatric population than does
creatinine
74 Finney, Newman, Thakkar, Fell, Price
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