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Articles |
1
Department of Clinical Biochemistry, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Turner St., London E1 2AD, UK.
2
Behringwerke AG, Postfach 1140, D-35001 Marburg,
Germany.
a Author for correspondence. Fax +(44) 171 377 1544; e-mail d.j.newman{at}mds.qmw.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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8.0 g/L), bilirubin (488 µL), triglycerides (23 mmol/L),
rheumatoid factor (2000 kIU/L), and myeloma paraprotein (41 g/L) do
not interfere with the assay. This assay agreed well with an in-house
particle-enhanced turbidimetric immunoassay (PETIA) (mean
difference = 1.73 ± 2.10) and a commercial PETIA (mean
difference = 1.13 ± 0.86). This is a new assay by which
cystatin C may be effectively used as a marker of GFR estimation.
Key Words: indexing terms: kidney function • immunoassay • glomerular filtration rate
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Introduction |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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Several other low-molecular-mass proteins,
ß2-microglobulin, retinol-binding protein, and
1-microglobulin (protein HC) have been investigated for
their utility in monitoring GFR (5)(8). None
of these has proven useful, mainly because of the influence of nonrenal
factors on their circulating concentrations; for example, infection,
dietary factors, and liver disease may vary their production rate
(5)(7).
Creatinine and urea are more commonly used for the clinical assessment of GFR but they too have a range of nonrenal factors influencing their production, for example, muscle mass and protein intake, and for creatinine there are several well-reported difficulties concerning its analysis (9)(10). An alternative to creatinine is needed that is analytically more reliable and as, or more, clinically reliable, i.e., a more sensitive and specific marker of nephron loss.
In previous years cystatin C measurement in serum has been suggested to correlate with GFR (4)(5)(7). Previous investigations have confirmed that the serum concentration of cystatin C is at least as good an indicator of GFR as the serum concentration of creatinine (4)(5)(7). For the introduction of this marker into clinical use a rapid and automated method is required.
The cystatin C concentration in biological fluids is low, making high
demands on the analytical sensitivity and specificity. In 1979,
Löfberg and Grubb (11) developed the first enzyme
immunoassay for quantifying cystatin C in human biological fluids and
later recommended this as a kidney function test (5). By
present standards, the assay was time consuming and had a poor
detection limit (see Table 1
). Subsequently, simpler and more-sensitive radio-,
fluorescence, and various enzyme immunoassays were developed to improve
analytical reliability of the methods. In 1993, Pergande and Jung
developed a sandwich enzyme immunoassay for determining cystatin C in
serum by using commercially available antibodies (17), but
the assay time was still far from ideal for routine processing,
especially urgent requests. Latex immunoassay is another nonisotopic
method based on direct agglutination by a protein of latex particles on
which a specific antibody has been conjugated. It is a homogeneous
method that can be easily automated. One assay based on latex particle
agglutination was the particle-counting immunoassay method used by
Bernard et al. (18), although no further detail is
specifically given on cystatin C measurement. In 1994–95, two fully
automated latex particle-enhanced turbidimetry assays for cystatin C
(19)(20) were developed. These assays are both
rapid, automated methods for measuring cystatin C.
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Here we describe the evaluation of a rapid automated method for determining serum and plasma concentrations of cystatin C on the basis of particle-enhanced nephelometry. This method has been compared with the two turbidimetric methods in a three-way method and calibrator comparison.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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There were two assays available for comparison with the proposed method. First was an in-house latex particle-enhanced immunoturbidimetry method performed on a Monarch 2000 centrifugal analyzer (Instrumentation Laboratory, Warrington, UK) operating at 37 °C. A tungsten lamp is used as the light source with the wavelength being produced by a scanning monochromator. Absorbance is monitored at 340 nm in a disposable cuvette rotor with a pathlength of 0.74 cm. The latex particles were prepared as described by Newman et al. (19) with rabbit anti-human cystatin C antiserum (Dakopatts, Copenhagen, Denmark; code no. A451) and 80-nm diameter chloromethyl styrene particles (Bangs Labs., Indianapolis, IN) (21). The calibrator was purified recombinant cystatin C (a gift from A. Grubb, Lund, Sweden) prepared according to Abrahamson et al. (22).
Second was the commercially available latex particle-enhanced turbidimetric immunoassay (PETIA) from Dakopatts (code no. 0071) performed on a Cobas Bio instrument (F. Hoffmann-La Roche, Basel, Switzerland), a single unit self-contained centrifugal analyzer operating at 37 °C. The light source is a high-intensity xenon flash in combination with a holographically inscribed grating monochromator. The change in absorbance at 340 nm was measured in a disposable cuvette rotor. This assay involved 38-nm carboxylate-modified latex particles obtained from Duke Scientific Corp., Palo Alto, CA, to which was conjugated the same rabbit anti-human cystatin C antiserum as above. The calibrator was purified human cystatin C assigned with recombinant cystatin C (22).
Serum creatinine was measured on samples used in the method comparison with the fixed-interval Jaffe method on the Monarch.
Final assay procedure.
The following optimal assay
protocol for measuring cystatin C was used in all experiments. All
dilutions are made with on-board diluent. The assay is performed at
room temperature with a six-point calibration curve (Fig. 1
) covering the range 0.23–7.25 mg/L (produced with an initial
lyophilized calibrator reconstituted with water). The calibrator is
sampled three times into predilution cups, resulting in seven
dilutions. All but the 1:10 dilution are used in the calibration curve.
Samples are prediluted to 1:100, in two stages, before being analyzed.
Fig. 2
shows how the neat sample is diluted before being pipetted into
a cuvette simultaneously with 10 µL of combined supplement reagent
(0.5 mL of reagent B is added to each bottle of reagent A), followed by
40 µL of particle reagent. Each calibrator dilution is pipetted in
the same way. The contents are mixed, with readings taken at 10 and
360 s. The change in the signal is converted into mg/L. A sample
can be measured in 6 min, with further results every 8 s.
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assay validation |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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Linearity.
Ten serum samples with high creatinine values
were diluted (1+9, 2+8... . 9+1) in isotonic (9 g/L) saline to
produce cystatin C values between 10% and 90% of the undiluted sample
to assess linearity.
Analytical recovery.
Analytical recovery was assessed
with two 450-µL aliquots of 10 different serum samples by using two
50-µL supplemented cystatin C concentrations (0.52 + 0.93 mg/L). The
percentage ratio between the measured and added concentrations of
cystatin C for each sample was calculated.
Analyte stability.
Twenty serum samples were obtained
and analyzed within 8 h of their collection. These samples were
aliquoted and stored at various temperatures: room temperature for 2
days, 4 °C for 1 week, -20 °C for at least 1 month, and
-20 °C with 10 freeze/thaw cycles before analysis.
Plasma vs serum.
The effect of anticoagulants was
assessed by collecting blood from 12 healthy subjects into plain,
heparin, and EDTA Vacutainer Tubes (Becton Dickinson, Franklin Lakes,
NJ). The appropriate serum and plasma fractions were assayed for
cystatin C. A further experiment with 19 matched serum and sodium
citrate anticoagulated plasma samples were also assayed for cystatin C.
Interferences.
The potential interferences of myeloma
paraproteins (7–41 g/L), rheumatoid factor (98.5–2000 kIU/L),
hemoglobin (1–8 g/L), bilirubin (38–488 µmol/L), and lipids
(5.33–23.13 mmol/L) was assessed by assaying 10 patient samples of
each increased interferent respectively and comparing any deviation
from true linearity. A dilution procedure was carried out in which each
sample was diluted (1+9, 2+8... 9+1, 10+0) with pooled patient serum
containing no potential interferences.
Method comparison.
A total of 120 patient samples was
assayed in duplicate for cystatin C and for creatinine with the methods
described. Each patient sample was obtained from the routine hospital
laboratory and chosen on the basis of creatinine values.
Statistical analysis.
Regression analyses were performed
with the "Astute" statistical package (Diagnostic Development Unit;
University of Leeds, Leeds, UK), as were the methods of Passing and
Bablok (23) and Bland and Altman (24) for
method comparison. The paired t-tests were performed with
Statview® Abacus Concepts (Berkeley, CA) for Macintosh
computers.
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Results |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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) covers
the range 0.23–7.25 mg/L over 6 calibration points.
Imprecision.
Imprecision (CV) was <3.3% (intraassay)
and <4.5% (interassay) across the assay range (Table 2
).
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Linearity.
The results obtained (x) did not
differ significantly from those expected (y) with the
regression analysis equation y = 0.18 +
0.94x (r2 = 0.997, n =
100), indicating no lack of parallelism.
Analytical recovery.
The average analytical recovery of
cystatin C for each added concentration (0.52 and 0.93 mg/L) was
95% ± 2.2% (1SD) and 109% ± 0.03% (1SD), respectively.
Analyte stability.
Although there was a 8% decrease in
value with a paired t-test (P <0.05), there was
no significant difference between fresh samples and those measured
after 2 days at room temperature, 1 week at 4 °C, or 1 week at
-20 °C; cystatin C was thus considered stable at all temperatures
over these time periods. However, there was a significant difference
(P <0.05) after 2 months at -20 °C, but the actual
change in values was <0.14 mg/L with no trend across the time period.
After 10 freeze/thaw cycles over 57 days there was a 15% decrease in
value. A paired t-test was calculated (P <0.05)
and showed statistical significance but no trend with time; the
greatest mean difference was 0.16 mg/L.
Plasma vs serum.
There was no significant difference
between EDTA and lithium heparin plasma cystatin C values. However,
there was a statistically significant (P <0.05) but small
(3%) difference between the serum and plasma cystatin C, EDTA plasma
having a bigger significant difference than lithium heparin plasma
values. A comparison between 19 matched serum and sodium citrate plasma
samples showed no significant difference after correction for sample
dilution due to the volume of sodium citrate anticoagulant. The 12
normal serum samples gave a cystatin C concentration range of
0.60–1.45 mg/L.
Interference tests.
Patient samples with hemoglobin
concentrations 8 g/L did not interfere with the assay. The greatest
deviation was 2.4% from the mean. Icteric patient samples with up to
488 µmol/L of bilirubin did not interfere, with the greatest
deviation being 3.2% from the mean. Samples with increased
triglyceride showed no interference with triglyceride as high as 23
mmol/L. The greatest deviation from the mean was 3.7%. Samples
containing increased rheumatoid factor concentrations (98.5–2000
kIU/L) showed no significant interference with the assay, the greatest
deviation being 5.1% from the mean. Samples with various myeloma types
were investigated for interference; none could be found in samples
containing up to 41 g/L paraprotein, with the greatest deviation of
5.0% from the mean.
Method comparison.
Samples (120) were measured in
duplicate in a three-way comparison with this cystatin C method
(Behring nephelometer system), an in-house cystatin C method (Monarch
2000), and a commercial cystatin C kit from Dakopatts (Cobas Bio,
Roche). Regression analysis (Passing and Bablok) were carried out on
each comparison (Fig. 3
). Regression for the particle-enhanced nephelometric
immunoassay (PENIA) = -0.15 + 0.77 x Dakopatts [intercept 95%
confidence interval (CI) = -0.21 to -0.12; slope 95% CI = 0.75
to 0.79] and 0.47 + 0.54 x in-house (intercept 95% CI =
0.44 to 0.47; slope CI = 0.54 to 0.55). Using the Bland and Altman
method as a predictor of scatter, the mean difference between the PENIA
and the in-house particle-enhanced turbidimetric immunoassay (PETIA)
was 1.73 ± 2.10 mg/L and between the PENIA and Dakopatts PETIA
was 1.13 ± 0.86 mg/L. For completeness, the agreement between the
Dakopatts and in-house PETIA methods was established: in-house =
-1.14 + 1.42 x Dakopatts (intercept 95% CI = -1.22 to
-1.10; slope 95% CI = 1.39 to 1.45) and the mean difference was
-0.50 ± 1.48 mg/L. Outliers 1 and 2 represent two samples that
show good precision between duplicates in all methods but do not
correlate well only in the Dakopatts assay. The only other information
known about these two samples was their creatinine values, 143 µmol/L
and 444 µmol/L, respectively. Overall there is excellent correlation
between the three methods. There were, however, differences between the
slopes and intercepts as shown above; much of this can be explained by
calibrator differences (see below). Fig. 4
shows the precision profile of each method. Although all three
methods show excellent performance, the Behring assay shows better
precision at <2.0 mg/L.
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Calibrators.
The three calibrators were from different
sources and had different assigned cystatin C values (Table 3
). Each calibrator was compared by measurement with each assay
for cystatin C. Taking the value of the Behring calibrator as 100%,
the calibrators from the Dakopatts and in-house methods as measured on
the Behring nephelometer system were recalculated as a percentage of
their respective assigned values. The Dakopatts calibrator was on
average 70% of its assigned value, whereas the in-house calibrator was
on average only 50% of its assigned value. When recalibrated, the
slopes of the in-house assay against the Behring assay changed from
0.54 to 1.09, the Dakopatts assay against the Behring assay changed
from 0.77 to 1.10, and the Dakopatts assay against the in-house assay
changed from 1.42 to 1.01, thereby identifying the calibrators as the
major source of the slope differences. Although the intercept between
the new PENIA method and the Dakopatts method showed no difference,
there was a 0.5 mg/L difference in the intercept between comparisons
with our in-house method and both other methods. The in-house method
has calibrator material contained in a horse serum matrix along with a
zero calibrator, unlike the PENIA and Dakopatts methods, whose lowest
calibrators are 0.23 and 0.42 mg/L, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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This latex particle assay for cystatin C was sensitive, with good recovery and linearity, and had no major interferences. Our results show that this PENIA method agrees well with existing PETIA methods (19)(20). Imprecision of 3–5% matches that of the in-house PETIA (19), whereas Kyhse-Anderson et al. reported average imprecision of 2.0–3.2% (20). The analyte had good stability in serum. We have shown that cystatin C is stable for 2 days at room temperature, 1 week at 4 °C, and 1 week at -20 °C. Although those measurements made after 2 months at -20 °C were statistically significant (P <0.05), the actual change in values showed no trend with time and was not very great, i.e., 3.27 to 3.13 mg/L. The assay is precise and the between-assay variation at this concentration (4.2% CV) would suggest that this difference (2.5SD = 0.34 mg/L) will not be of clinical significance. Measuring cystatin C concentrations over 10 freeze/thaw cycles did not show any trends that were clinically or statistically significant. Kyhse-Anderson et al. (20) reported stability for only 5 days at 4 °C and three cycles of freeze/thaw, whereas Newman et al. (19) only reported on overnight stability at 4 °C and -20 °C.
Heparin and EDTA showed a statistically significant interference in cystatin C concentration in serum; the between-assay variation at this concentration (3.6%) would also suggest that this difference of 0.02 mg/L (2.5SD = 0.05 mg/L) will not be of clinical significance. However, although the cystatin C concentration in sodium citrate-anticoagulated plasma was 10% lower than serum-matched samples, these results can be accounted for by dilutional effects from the 1:10 ratio of anticoagulant to serum volume used in these Vacutainer Tubes.
The PENIA method shows less interference than those reported in the two
PETIA methods (19)(20): hemoglobin (1.0 g/L,
1.2 g/L), bilirubin (300 µmol/L, <150 µmol/L), triglycerides
(10 mmol/L, 8.5 mmol/L), and rheumatoid factor (increased
concentrations, 3230 kIU/L). Kyhse-Anderson et al. reported bilirubin
interferences at 150–300 µmol/L, whereas we did not find this to be
the case. We demonstrated that grossly hemolytic and lipemic samples do
not interfere with this assay. Increased concentrations of rheumatoid
factor showed no interference; neither did increased paraprotein
concentrations.
Nephelometric assays have always been proposed as being potentially more sensitive than turbidimetric assays. Nephelometry monitors an increase in light intensity against a low background signal, and this gives nephelometric detection a theoretical edge. In practice, however, nonspecific background scatter in biological samples has required high sample predilutions, thus reducing the achievable detection limits to those of turbidimetric assays. Here we use a sample predilution that gives a lower sample fraction in the assay of 0.38% compared with the two turbidimetric assays (1.19% and 3.57%) with reduced interferences. There are other differences between the different methods, i.e., particles and antibody used; however, it is interesting to note that the PENIA appears to show less spectrophotometric interference and roughly equal imprecision and performance.
Comparison of this cystatin C assay with the two others, the in-house
assay (mean difference = 1.73 ± 2.10) and the Dakopatts
assay (mean difference = 1.13 ± 0.86), was good, with very
few outliers (Fig. 3
). Although there was a difference in slopes and
intercepts, these could be accounted for when comparing the
disagreement between the calibrator potencies and matrices of the three
methods. On the Behring nephelometer system the recombinant protein
calibrator was 50% of its assigned value, whereas the Dakopatts
calibrator was 70%. Recalibration with the new assigned values allowed
the slopes to become equal to 1.0. The disagreement in calibrator
potencies must be due to the differences between recombinant and
purified materials. Cystatin C does not have any glycosylation variance
between materials; however, there may be unknown variations introduced
during purification of cystatin C causing potency differences. Whatever
the disagreement, a primary calibrator is required that can be an
arbiter to assign secondary calibrators for measurement of cystatin C.
This new marker requires an internationally agreed-upon reference
preparation to allow direct comparison between methods and for future
reporting of reference ranges. Pergande and Jung (17)
reported a difference between male and female reference ranges (Table 1
) with a urinary protein calibrator from Behringwerke; others did not
find any significant sex differences (15)(20).
Our preliminary data are in agreement with Kyhse-Andersen et al.
(20) and with the work of Löfberg and Grubb
(11), but further studies to establish a comprehensive
reference range are necessary to explore whether there are no sex and
age differences in cystatin C concentrations in a healthy population.
The nephelometer takes only ~10 s to dilute and transfer one sample to a cuvette, with a reading taken after 6 min. All samples in any one batch, up to a maximum of 75 samples, have to be diluted to 1:100 before the probe returns to the first diluted sample for transfer to a cuvette, obviously increasing the assay time for large batches. Having been mixed with the reagents, the sample has a 6-min countdown before the reaction is completed. Each subsequent sample reading is available after 8 s. The sample volume used to make the first dilution is 80 µL. This is rather a large volume compared with 20 µL (Kyhse-Anderson et al. (20)) and 5 µL (Newman et al. (19)) and may be problematic for small-volume samples, i.e., patients in intensive therapy units and pediatrics.
The method comparison of 120 samples produced two outliers that could
not be accounted for by analytical errors, and, unfortunately, because
of a lack of patient information apart from creatinine values, no
medical records could be searched for any clues to the poor correlation
of either sample. However, the outliers showed up on only two of the
three comparisons (Fig. 3
), the common link being the Dakopatts method.
Whereas both the in-house and Dakopatts assays share the same antibody,
they do differ in the particles used, 80-nm chloromethyl styrene vs
38-nm carboxylate-modified particles. Whether the different conjugation
procedures and particle surfaces contribute to such discrepancies is
not known.
In conclusion, this new cystatin C assay was found to be a robust, fully automated, and rapid method, essential for the quick turnaround necessary in a routine hospital laboratory. Whereas other methods are adapted for routine turbidimetric analyzers, this method is specific for a nephelometric analyzer. A full age-related, sex-related reference range, with body mass indices, needs to be determined with this method and compared with others. Additionally, further prospective studies are required to monitor cystatin C concentration in patients with different renal pathologies, e.g., diabetic nephropathy to assess cystatin C as a potentially more sensitive and specific marker of GFR than creatinine.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and Methodsassay validationResultsDiscussionReferences |
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-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis. Proc Natl Acad Sci U S A 1982;79:3024-3027.
-trace (cystatin C) among the cysteine proteinase inhibitors. Biochem Biophys Res Commun 1984;120:631-636.
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-trace) as a measure of the glomerular filtration rate. Scand J Clin Lab Invest 1985;45:97-101.
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1-microglobulin in the assessment of renal function. Ann Clin Biochem 1991;28:514-516.
-trace in human biological fluids: indications for production in the central nervous system. Scand J Clin Lab Invest 1979;39:619-626.
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globulin) in serum from patients with autoimmune diseases. Turk V eds. Cysteine proteinases and their inhibitors 1986:507-516 Walter de Gruyter Berlin. .
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O. F. Laterza, C. P. Price, and M. G. Scott Cystatin C: An Improved Estimator of Glomerular Filtration Rate? Clin. Chem., May 1, 2002; 48(5): 699 - 707. [Abstract] [Full Text] [PDF]
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 A L Gerbes, V Gulberg, M Bilzer, and M Vogeser Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver Gut, January 1, 2002; 50(1): 106 - 110. [Abstract] [Full Text] [PDF]
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E. J. Uhlmann, K. G. Hock, C. Issitt, M. R. Sneeringer, D. R. Cervelli, R. T. Gorman, and M. G. Scott Reference Intervals for Plasma Cystatin C in Healthy Volunteers and Renal Patients, as Measured by the Dade Behring BN II System, and Correlation with Creatinine Clin. Chem., November 1, 2001; 47(11): 2031 - 2033. [Full Text] [PDF]
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H. Stowe, D. Lawrence, D. J. Newman, and E. J. Lamb Analytical Performance of a Particle-enhanced Nephelometric Immunoassay for Serum Cystatin C Using Rate Analysis Clin. Chem., August 1, 2001; 47(8): 1482 - 1485. [Full Text] [PDF]
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M. A. Serdar, I. Kurt, F. Ozcelik, M. Urhan, S. Ilgan, M. Yenicesu, L. Kenar, and T. Kutluay A Practical Approach to Glomerular Filtration Rate Measurements: Creatinine Clearance Estimation Using Cimetidine Ann. Clin. Lab. Sci., July 1, 2001; 31(3): 265 - 273. [Abstract] [Full Text] [PDF]
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 H Finney, D J Newman, H Thakkar, J M E Fell, and C P Price Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children Arch. Dis. Child., January 1, 2000; 82(1): 71 - 75. [Abstract] [Full Text]
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T. Le Bricon, E. Thervet, M. Benlakehal, B. Bousquet, C. Legendre, and D. Erlich Changes in Plasma Cystatin C after Renal Transplantation and Acute Rejection in Adults Clin. Chem., December 1, 1999; 45(12): 2243 - 2249. [Abstract] [Full Text] [PDF]
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F. Muller, M.-A. Bernard, A. Benkirane, S. Ngo, S. Lortat-Jacob, J.-F. Oury, and M. Dommergues Fetal Urine Cystatin C as a Predictor of Postnatal Renal Function in Bilateral Uropathies Clin. Chem., December 1, 1999; 45(12): 2292 - 2293. [Full Text] [PDF]
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E. Randers, S. Krue, E. J. Erlandsen, H. Danielsen, and L. G. Hansen Reference Interval for Serum Cystatin C in Children Clin. Chem., October 1, 1999; 45(10): 1856 - 1858. [Full Text] [PDF]
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S. Guaita, J. M. Simo, N. Ferre, J. Joven, and J. Camps Evaluation of a Particle-enhanced Turbidimetric Immunoassay for the Measurement of Immunoglobulin E in an ILab 900 Analyzer Clin. Chem., September 1, 1999; 45(9): 1557 - 1561. [Abstract] [Full Text] [PDF]
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L. Risch, A. Blumberg, and A. Huber Rapid and accurate assessment of glomerular filtration rate in patients with renal transplants using serum cystatin C Nephrol. Dial. Transplant., August 1, 1999; 14(8): 1991 - 1996. [Abstract] [Full Text] [PDF]
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D. Newman and J. Kos More on Cystatin C • One of the authors of the article cited above responds: Clin. Chem., May 1, 1999; 45(5): 718 - 719. [Full Text] [PDF]
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F. Priem, H. Althaus, M. Birnbaum, P. Sinha, H. S. Conradt, and K. Jung ß-Trace Protein in Serum: A New Marker of Glomerular Filtration Rate in the Creatinine-Blind Range Clin. Chem., April 1, 1999; 45(4): 567 - 568. [Full Text] [PDF]
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J. Kos, B. Stabuc, N. Cimerman, and N. Brunner Serum Cystatin C, a New Marker of Glomerular Filtration Rate, Is Increased during Malignant Progression Clin. Chem., December 1, 1998; 44(12): 2556 - 2557. [Full Text] [PDF]
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B. G. Keevil, E. S. Kilpatrick, S. P. Nichols, and P. W. Maylor Biological variation of cystatin C: implications for the assessment of glomerular filtration rate Clin. Chem., July 1, 1998; 44(7): 1535 - 1539. [Abstract] [Full Text] [PDF]
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D. Stickle, B. Cole, K. Hock, K. A. Hruska, and M. G. Scott Correlation of plasma concentrations of cystatin C and creatinine to inulin clearance in a pediatric population Clin. Chem., June 1, 1998; 44(6): 1334 - 1338. [Abstract] [Full Text] [PDF]
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S. K. Swan The Search Continues--An Ideal Marker of GFR Clin. Chem., June 1, 1997; 43(6): 913 - 914. [Full Text] [PDF]
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