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Technical Briefs |
1
Medizinische Klinik und Poliklinik I, Allgemeine Innere Medizin
2
Institute of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany
a author for
correspondence: fax 49-228-287-4323, e-mail Woitas{at}uni-bonn.de
The gold standard for the evaluation of the glomerular filtration rate (GFR) is inulin clearance (CIn), but its widespread use is prevented by several technical difficulties (1). The most commonly used marker for GFR is serum creatinine. However, serum creatinine concentrations should be interpreted with caution as a filtration marker in liver cirrhosis because they do not adequately reflect renal dysfunction. Increased tubular secretion and muscle wasting account for the disparity between creatinine concentrations and GFR in cirrhotic patients (2)(3)(4). Thus, GFR has been demonstrated repeatedly to be overestimated by serum creatinine (1)(2)(3)(4)(5).
Cystatin C, a cationic 13-kDa protein that is produced by nucleated cells and catabolized by the renal tubular cells after passing the glomerular filter, has recently been reported as a reliable endogenous marker of GFR in healthy adults and children as well as in patients with nephrologic, urologic, and rheumatologic disorders (6)(7)(8)(9). For patients with liver cirrhosis, however, no data are available. Therefore, we studied cystatin C in comparison to creatinine for the assessment of GFR in these patients. We also determined the precision (10) of each analyte to predict GFR in cirrhotic patients.
Forty-four patients with liver cirrhosis who were classified according
to the Child–Pugh criteria [serum bilirubin, prothrombin time, serum
albumin, ascites, and encephalopathy (11)] had
their GFRs determined by steady-state CIn. All patients had
evidence of portal hypertension indicated by esophageal varices,
ascites, and characteristic features of liver cirrhosis by ultrasound
(Table 1
). The causes of liver disease were alcoholism (n = 31),
viral hepatitis (n = 10), and other liver diseases (n = 3).
No patient had evidence of renal disease as assessed by examination of
urinary sediment and proteinuria.
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Informed consent was obtained from all subjects, and the study protocol was approved by the local ethics committee.
Because food intake may bias renal function, GFR was tested after an overnight fasting period in the supine position. CIn studies on urine and blood samples were conducted as described elsewhere, and results were adjusted to a standard body surface of 1.73 m2 (12). Serum creatinine was determined on the DimensionTM clinical chemistry system (Dade Behring) with a commercial assay based on the Jaffe method. The detection limit was 4 µmol/L, defined as the concentration 2 SD above the CHEM I calibrator (Dade Behring) at 0 µmol/L creatinine (n = 20). The intraassay CV was 1% (mean, 61 µmol/L; n = 20), and the interassay CV was 2.5% (79.4 µmol/L; n = 20).
Serum cystatin C was analyzed by a fully automated latex-enhanced immunonephelometric method (N Latex Cystatin C Nephelometer II; Dade Behring). The detection limit of the assay was 0.05 mg/L with an intraassay CV of 1.9% (mean, 0.6 mg/L; n = 20), and an interassay CV of 3.6% (mean, 0.6 mg/L; n = 20). Reference intervals established from a population of 100 healthy male (median age, 35.5 years; 5th to 95th percentile, 20–60 years) and 100 healthy female (median age, 27 years; 5th to 95th percentiles, 19–55 years) blood donors were 0.5–0.82 mg/L (2.5th to 97.5th percentiles) for males and 0.5–0.74 mg/L for females; for creatinine, the reference intervals were 71–115 µmol/L for males and 53–88.4 µmol/L for females.
Statistical analysis was performed using Statview 4.5 for Macintosh (Abacus Concepts) and MedCalc for Windows (Mariakerke). Predictive performance was analyzed according to the method of Sheiner and Beal (10). P <0.05 (two-tailed) was considered significant.
Almost all patients exhibited a considerably reduced GFR (mean ±
SD, 36.8 ± 21.7 mL · min-1 · 1.73
m-2; median, 32.6
mL · min-1 · 1.73
m-2). The decrease appeared to be less
pronounced in Child A cirrhosis, although the difference was not
statistically significant (Table 1
). Patients with Child C and B
cirrhosis had slightly higher values than patients with Child A
cirrhosis (P = 0.1, Kruskal–Wallis test). Cystatin C
was significantly higher in patients with Child B and C cirrhosis than
in those with Child A cirrhosis (Table 1
), whereas no differences were
noted between patients with Child B and C cirrhosis.
The reciprocals of the creatinine and cystatin C concentrations
(1/creatinine and 1/cystatin C) correlated significantly: 1/cystatin C
(L/mg) = 0.37 + 45.47[1/creatinine (L/µmol)];
r = 0.662 (95% confidence interval, 0.458–0.801);
z-statistic, 5.1; P <0.0001. However,
only 1/cystatin C (Fig. 1
A), but not 1/serum creatinine, was significantly correlated
with the GFR (Fig. 1B
). The comparison of correlation coefficients
revealed a significant difference between the two analytes in favor of
1/cystatin C (P = 0.021; z-statistic =
-2.30).
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To test the ability (10) of each analyte to predict GFR, we derived the following equations: GFRcystatinC (mL · min-1 · 1.73 m-2) = 3.7 + 34.6 [1/cystatin C (L/mg)]; and GFRcreatinine (mL · min-1 · 1.73 m-2) = 23.9 + 1003.9 [1/creatinine (L/µmol)]. The predictive precision of 1/cystatin C to estimate the GFR was slightly better (root mean-squared prediction error, 16.1 vs 20.6 mL · min-1 · 1.73 m-2; not significant) than that of 1/creatinine.
When we used a GFR of 90 mL · min-1 · 1.73 m-2 as cutoff, 42 patients had an impaired GFR. Cystatin C showed a significantly higher sensitivity for detecting a reduced GFR than did creatinine (85.7% vs 28.5%; P = 0.045, McNemar test).
Because many patients with cirrhosis and ascites have a reduced GFR but normal serum creatinine, alternative and reliable markers of GFR are needed (13)(14)(15). Our analysis of 44 patients with liver cirrhosis demonstrates a significantly better correlation with the GFR for 1/cystatin C than for 1/creatinine. Most importantly, cystatin C shows a significantly higher sensitivity for detecting reduced GFR. Edema and ascites do not appear to influence the creatinine or cystatin C concentrations because control investigations showed similar concentrations of the analytes in serum and ascites (data not shown).
Analysis of serum creatinine is an inexpensive and rapid tool to estimate GFR in daily practice. However, for the above-mentioned reasons, creatinine may overestimate GFR in cirrhotics (1)(3)(4)(5). In fact, in our cohort, 25 of 38 patients (65.78%) with a GFR <60 mL · min-1 · 1.73 m-2 exhibited normal creatinine values.
CIn, which is widely regarded as the gold standard for determination of GFR, is impractical because of the necessity for steady-state infusion, a urine bladder catheter, and possible interference from blood glucose (1). Although other plasma-clearance techniques, such as 99mTc-diethylenetriaminepentaacetate have been used for estimation of GFR (16)(17)(18)(19), it should be kept in mind that all plasma-clearance techniques become somewhat inaccurate when renal disease progresses to GFR values below 20–30 mL · min-1 · 1.73 m-2 (20).
Cystatin C is proposed to reflect GFR independent of age, height, and body composition (21)(22)(23)(24). Recently, Kos and co-workers (25)(26) described an increase in the relative amount of cystatin C in malignant diseases such as colorectal cancer or melanoma. However, it should be stressed that these studies were carried out without a reference technique for measuring GFR (27) and thus cannot provide definite evidence that nonrenal factors affect serum concentrations of cystatin C.
In our cohort, the correlation coefficients for the reciprocals of serum cystatin C with creatinine and GFR were in the range of previous studies (6)(7)(9)(28)(29)(30)(31). Some investigators found that cystatin C provides both better analytical performance and improved sensitivity in detecting early renal function loss (6)(9)(31)(32)(33), whereas other investigators did not (7)(28)(30).
We found a significant diagnostic advantage in using cystatin C
serum measurements to detect a reduced GFR in cirrhotics; this was true
mainly for patients with Child B and C cirrhosis exhibiting advanced
GFR impairment (Fig. 1
).
In Fig. 1
, several values, including some for 1/cystatin C, were far
off from a close correlation with the GFR. The reason for this
skewing in some patients is difficult to explain because the patients
did not differ with respect to the degree of liver failure or special
treatments. However, despite the fact that cystatin C correlated better
with the GFR in general than did creatinine, a recent publication
showed that both analytes exhibit similar CVs at low GFR values
(34).
In conclusion, our study shows that the sensitivity of serum cystatin C for detecting reduced GFR is higher than that of creatinine in patients with liver cirrhosis. Therefore, serum cystatin C measurements may be useful in these patients. However, neither serum cystatin C nor creatinine reliably allows the prediction of the exact GFR in these patients.
Acknowledgments
We thank A. Carstensen, D. Ehlert, M. Schmidt, and U. Schmitz for excellent technical assistance in performing clearance, creatinine, and cystatin C measurements. We also thank Dr. R. Fimmers, Institute for Medical Statistics University of Bonn, Bonn, Germany for statistical support and helpful discussions, and Dr. A. Bökenkamp, Universitätskinderklinik Bonn, Bonn, Germany for helpful discussion and critical review of the manuscript.
References
The following articles in journals at HighWire Press have cited this article:
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  S. Gourishankar, M. Courtney, G. S. Jhangri, G. Cembrowski, and N. Pannu Serum cystatin C performs similarly to traditional markers of kidney function in the evaluation of donor kidney function prior to and following unilateral nephrectomy Nephrol. Dial. Transplant., September 1, 2008; 23(9): 3004 - 3009. [Abstract] [Full Text] [PDF]
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U. Poge, T. Gerhardt, B. Stoffel-Wagner, H. U. Klehr, T. Sauerbruch, and R. P. Woitas Calculation of glomerular filtration rate based on Cystatin C in cirrhotic patients Nephrol. Dial. Transplant., March 1, 2006; 21(3): 660 - 664. [Abstract] [Full Text] [PDF]
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 U. Poge, T. M. Gerhardt, B. Stoffel-Wagner, H. Palmedo, H.-U. Klehr, T. Sauerbruch, and R. P. Woitas {beta}-Trace Protein Is an Alternative Marker for Glomerular Filtration Rate in Renal Transplantation Patients Clin. Chem., August 1, 2005; 51(8): 1531 - 1533. [Full Text] [PDF]
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W. Koenig, D. Twardella, H. Brenner, and D. Rothenbacher Plasma Concentrations of Cystatin C in Patients with Coronary Heart Disease and Risk for Secondary Cardiovascular Events: More than Simply a Marker of Glomerular Filtration Rate Clin. Chem., February 1, 2005; 51(2): 321 - 327. [Abstract] [Full Text] [PDF]
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R. Orlando, M. Mussap, M. Plebani, P. Piccoli, S. De Martin, M. Floreani, R. Padrini, and P. Palatini Diagnostic Value of Plasma Cystatin C as a Glomerular Filtration Marker in Decompensated Liver Cirrhosis Clin. Chem., June 1, 2002; 48(6): 850 - 858. [Abstract] [Full Text] [PDF]
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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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R. P. Woitas, B. Stoffel-Wagner, U. Poege, P. Schiedermaier, U. Spengler, and T. Sauerbruch Low-Molecular Weight Proteins as Markers for Glomerular Filtration Rate Clin. Chem., December 1, 2001; 47(12): 2179 - 2180. [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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L. Risch, R. Herklotz, A. Blumberg, and A. R. Huber Effects of Glucocorticoid Immunosuppression on Serum Cystatin C Concentrations in Renal Transplant Patients Clin. Chem., November 1, 2001; 47(11): 2055 - 2059. [Full Text] [PDF]
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, Child A; 
, Child B; 
, Child C. The cutoffs for healthy
individuals are indicated by the dashed
lines. The shaded areas represent the
pathologic ranges. Linear regression analysis gave: (A),
1/cystatin C (L/mg) = 0.49 + 0.01 [GFR
(mL · min-1 · 1.73 m-2)];
r = 0.661 (95% confidence interval, 0.452–0.80);
P <0.0001; and (B), 1/creatinine
(L/µmol) = 0.01 + 7.77 x 10-5 [GFR
(mL · min-1 · 1.73 m-2)];
r = 0.279 (95% confidence interval, -0.019 to
0.532); P = 0.0662.