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NDT Advance Access originally published online on March 8, 2006
Nephrology Dialysis Transplantation 2006 21(7):1855-1862; doi:10.1093/ndt/gfl073
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function

Radovan Hojs1, Sebastjan Bevc1, Robert Ekart1, Maksimiljan Gorenjak3 and Ludvik Puklavec2

1 Department of Nephrology and 2 Department of Nuclear Medicine, Clinical Department of Internal Medicine and 3 Department of Clinical Chemistry, Teaching Hospital Maribor, Maribor, Slovenia

Correspondence and offprint requests to: Prof. Radovan Hojs, MD, PhD, Splosna bolnisnica Maribor, Klinicni oddelek za interno medicino, Oddelek za nefrologijo, Ljubljanska 5, 2000 Maribor, Slovenia. Email: Radovan.Hojs{at}sb-mb.si



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Estimation of the glomerular filtration rate (GFR) is essential for the evaluation of patients with chronic kidney disease (CKD). Recently, serum cystatin C was proposed as a new endogenous marker of GFR and in our study its diagnostic accuracy was compared with that of other markers of GFR.

Methods. In this study, 164 patients with CKD stages 2–3 (GFR 30–89 ml/min/1.73 m2), who had performed 51Cr-labelled ethylenediaminetetra-acetic acid clearance, were enrolled. In each patient, serum creatinine and serum cystatin C were determined. Creatinine clearance was calculated using the Cockcroft–Gault (C&G) and the modification of diet in renal disease (MDRD) formulas.

Results. The mean 51CrEDTA clearance was 57 ml/min/1.73 m2, the mean serum creatinine 149 µmol/l and the mean serum cystatin C 1.74 mg/l. We found significant correlation between 51CrEDTA clearance and serum creatinine (R = –0.666), serum cystatin C (R = –0.792), reciprocal of serum creatinine (R = 0.628), reciprocal of serum cystatin C (R = 0.753) and calculated creatinine clearance from the formulas C&G (R = 0.515) and MDRD formulas (R = 0.716). The receiver operating characteristic (ROC) curve analysis (cut-off for GFR 60 ml/min/1.73 m2) showed that serum cystatin C had a significantly higher diagnostic accuracy than serum creatinine (P = 0.04) and calculated creatinine clearance from the C&G formula (P<0.0001), though only in female patients. No difference in diagnostic accuracy was found between serum cystatin C and creatinine clearance calculated from the MDRD formula.

Conclusions. Our results indicate that serum cystatin C is a reliable marker of GFR in patients with mildly to moderately impaired kidney function and has a higher diagnostic accuracy than serum creatinine and calculated creatinine clearance from the C&G formula in female patients.

Keywords: 51CrEDTA clearance; chronic kidney disease; glomerular filtration rate; serum creatinine; serum cystatin C



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Chronic kidney disease (CKD) is an important public health problem and estimation of the glomerular filtration rate (GFR) is essential for the evaluation of patients with CKD. The current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines stratify CKD into five stages, also on the basis of GFR estimations [1]. Mild reduction in GFR was defined as CKD only in the presence of kidney damage (stage 2 of CKD; GFR 89–60 ml/min/1.73 m2). Moderate (stage 3 of CKD; GFR 59–30 ml/min/1.73 m2) to severe (stage 4 of CKD; GFR 29–15 ml/min/1.73 m2) reduction in GFR and kidney failure (stage 5 of CKD; GFR <15 ml/min/1.73 m2) were defined as CKD, irrespective of the presence of kidney damage.

The ideal marker of GFR should be an endogenous molecule which, being produced at a constant rate, is cleared solely by the kidneys via free glomerular filtration, with being neither secreted by tubular cells, nor reabsorbed into peritubular circulation [2]. The ‘gold standard’ for estimation of GFR is clearance of exogenous substances such as inulin, iohexol, 51CrEDTA, 99mTcDTPA or [125I]-iothalamate. These techniques are time-consuming, labour-intensive, expensive and require administration of substances that make them incompatible with routine monitoring. In many European countries, the standard method for the estimation of GFR is 51CrEDTA clearance with a single bolus of 51CrEDTA, which is comparable with inulin clearance.

During the last decades, in clinical practice as in most studies, serum creatinine concentration has become the most commonly used marker to estimate GFR. Creatinine is completely filtered across the glomerular membrane, and is neither reabsorbed nor metabolized in the kidneys and is partially secreted into the proximal tubule. Tubular secretion causes the increase of creatinine clearance by 10–20% [3]. Creatinine is usually measured by the Jaffé reaction, based on a complex formation between alkaline picrate and creatinine. According to this method, other non-creatinine cromogens are present in serum, which are not found in urine. Thus, creatinine concentration is overestimated in serum and the calculated clearance is underestimated (by 10–20%). In individuals with normal renal function both irregularities are abolished and creatinine clearance is very close to the inulin clearance. Other factors, including age, gender, race, body size, muscle mass and food intake (meat in diet), also affect the serum creatinine concentration. Creatinine clearance gives a better estimate of GFR than serum creatinine concentration, but it requires the inconvenience of urine collection. The current K/DOQI guidelines emphasize the need to assess kidney function using predictive equations rather than just serum creatinine [1]. The Cockcroft–Gault (C&G) formula is widely used in Europe to estimate the creatinine clearance from serum creatinine concentration, with correction for age, muscle mass and sex [4]. Another widely used formula is the modification of diet in renal disease (MDRD) formula [4]. This four-variable equation uses serum creatinine in combination with age, sex and race to estimate GFR. All these formulas are also limited by lack of validation in the full range of GFR to which they are applied [5]. Common features of these equations are reliance on serum creatinine and demographic and anthropometric data [1,5]. The accuracy of these formulas is still debated.

Recently, serum cystatin C was proposed as a new endogenous marker of GFR. This protease inhibitor with a low molecular weight is produced at a constant rate by all nucleated cells. It is freely filtered across the glomerular membrane and is reabsorbed and metabolized in the proximal tubule [6]. Serum cystatin C does not depend on muscle mass, sex and age [7]. Extra renal clearance rate of cystatin C was 0.34 ml/min in the study of Tenstad et al. [8], and this corresponds approximately to 13% of the normal GFR in the rat. Serum cystatin C concentration is not affected by inflammation, fever and/or outside agents [6]. There is contradictory data concerning the possible influence of malignant diseases on the serum concentration of cystatin C, however, most authors are of the opinion that malignant processes do not influence serum cystatin C concentration [6,9]. Serum cystatin C concentration is a better indicator of GFR than serum creatinine concentration in patients with spinal injury, liver cirrhosis or diabetes and in elderly patients [10,11]. Considering known facts in clinical practice, serum cystatin C could be a better indicator of GFR than serum creatinine concentration in patients with CKD, at least in patients with mild to moderate impairment renal function.

The aim of our study was to compare serum creatinine and serum cystatin C with 51CrEDTA clearance in a population of patients with mild (stage 2 of CKD) to moderate (stage 3 of CKD) impairment kidney function. We also compared serum cystatin C and creatinine clearance calculated from the C&G and MDRD formulas with 51CrEDTA clearance in the same patients.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
In our study, 164 patients with CKD stages 2–3 (GFR 30–89 ml/min/1.73 m2) who had performed 51CrEDTA clearance were enrolled. All patients were referred for 51CrEDTA clearance because of suspected or established renal dysfunction. Patients with CKD stage 1 (normal or preserved GFR and structural/functional abnormalities) and stages 4–5 (GFR <30 ml/min/1.73 m2) were excluded. Of the total patients, 78 (47.6%) were women and 86 (52.4%) were men. The age of patients ranged from 14 to 86 years, giving a mean of 57.5 years. Their heights ranged from 142 to 187 cm and the mean height was 168 cm. The mean weight was 77.5 kg with patients ranging from 46 to 142 kg.

In all patients included in the study, 51CrEDTA clearance was estimated. At the same time 51CrEDTA clearance was estimated, serum creatinine and serum cystatin C were also measured. Serum creatinine was measured by using the kinetic method according to the Jaffé method without deproteinization (Roche Diagnostics). This is a compensated method based on manufacturer instructions and was described previously [12]. Serum cystatin C was measured by the particle-enhanced immunonephelometric method (Dade Behring). The GFR was estimated from a single 51CrEDTA injection and three blood samples (120, 180 and 240 min after parenteral application of the marker) according to The Committee on Renal Clearance recommendations [13]. 51CrEDTA clearance was calculated in millilitre per minute per 1.73 m2. Creatinine clearance was calculated according to C&G (I) and MDRD formula (II):

(I) Creatinine clearance calculated according to C&G formula:

Formula
The correction factor of 0.85 was used for women.

(II) Creatinine clearance calculated according to MDRD formula:

Formula
The correction factor of 0.742 was used for women.

The C&G formula was standardized for a 1.73 m2 body surface area (according to DuBois and DuBois method); the MDRD formula is already standardized for a 1.73 m2 body surface area. In statistical analysis, SPSS for Windows (version 12.0.1) and MedCalc for Windows (version 5.00.020) were used. Mean values, range and SD were calculated. The Mann–Whitney test was used to define differences between genders, considering the values of 51CrEDTA clearance, serum creatinine and serum cystatin C concentration and creatinine clearance calculated from the formulas C&G and MDRD formulas. Pearson's correlation coefficient was used for defining the correlation between 51CrEDTA clearance and reciprocal of serum creatinine and reciprocal of serum cystatin C and also the creatinine clearance calculated from the formulas C&G and MDRD formula. The Spearman's rank correlation coefficient was used for defining the correlation between 51CrEDTA clearance and serum creatinine and serum cystatin C. In order to determine the diagnostic accuracy of cystatin C in comparison with the other markers of GFR, receiver operating characteristic (ROC) plots were constructed and analysed. The area under the curve describes the test's overall performance and is used to compare different tests. Sensitivity and specificity were calculated. The GFR, determined with 51CrEDTA, was used as the gold standard and the cut-off value was set at 60 ml/min/1.73 m2 (value distinguishing between mildly and moderately reduced GFR). To compare the creatinine-based estimations of GFR (C&G and MDRD formulas) with 51CrEDTA clearance, Bland and Altman plots were used [14]. The mean difference between estimated and measured GFR values estimates the global bias. The width of the SD of the mean difference is an estimation of precision.

The study protocol was in conformity with ethical guidelines and informed consent was obtained from each participant.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Mean 51CrEDTA clearance in our patients was 57 ml/min/1.73 m2, and ranged from 30 to 89 ml/min/1.73 m2 (SD±18). Mean serum creatinine concentration value was 149 µmol/l, ranging from 79 to 651 µmol/l (SD±64). Serum cystatin C concentration values were between 0.59 and 5.37 mg/l, and the mean value was 1.74 mg/l (SD±0.81). There was no statistically significant difference between genders considering the values of 51CrEDTA clearance (P = 0.261), serum cystatin C concentration (P = 0.846) and creatinine clearance calculated from the MDRD formula (P = 0.121). The values of serum creatinine concentration were statistically significantly higher in men (159.5 vs 137.4 µmol/l, P<0.0001) and the values of creatinine clearance calculated from the C&G formula were also statistically significantly higher in men (66.5 vs 47.9 ml/min/1.73 m2, P<0.0001). Statistically significant correlation was found between 51CrEDTA clearance and serum creatinine (R = –0.666; P<0.0001), serum cystatin C (R = –0.792; P<0.0001), reciprocal of serum creatinine (R = 0.628; P<0.0001), reciprocal of serum cystatin C (R = 0.753; P<0.0001) and also with creatinine clearance calculated from the C&G (R = 0.515; P<0.0001) and MDRD formulas (R = 0.716; P<0.0001). Linear regression plots between 51CrEDTA clearance and reciprocal of serum creatinine and reciprocal of serum cystatin C for all patients included in the study and separately for women and men are shown in Figures 1 and 2. The linear regression statistics for the C&G and MDRD formulas are shown in Table 1. Diagnostic accuracy (area under the ROC curves, sensitivity and specificity) at cut-off value for GFR 60 ml/min/1.73 m2 of different tests, are presented in Table 2. ROC curve analysis for all patients included in the study showed that serum cystatin C had significantly higher diagnostic accuracy than serum creatinine and creatinine clearance calculated from the C&G formula. No difference in diagnostic accuracy was found between serum cystatin C and creatinine clearance calculated from the MDRD formula. Creatinine clearance calculated from the MDRD formula had significantly higher diagnostic accuracy than creatinine clearance calculated from the C&G formula (P<0.0001). Diagnostic accuracy for all patients included in the study is shown in Figure 3. ROC curve analysis was also performed for both men and women. In women, serum cystatin C had significantly higher diagnostic accuracy than serum creatinine and creatinine clearance calculated from the C&G formula but not higher for the creatinine clearance calculated from the MDRD formula. In men, no difference was found between serum cystatin C and serum creatinine and creatinine clearance calculated from the MDRD formula. Serum cystatin C had significantly higher diagnostic accuracy than creatinine clearance calculated from the C&G formula. Creatinine clearance calculated from the MDRD formula had significantly higher diagnostic accuracy than creatinine clearance calculated from the C&G formula, both in men (P<0.001) and in women (P<0.01). The mean difference, calculated according to Bland and Altman [14], between calculated GFR from the C&G formula and measured GFR with the reference method (51CrEDTA clearance) was 0.6 ml/min/1.73 m2 (P = 0.79) (Figure 4). The mean difference between calculated GFR from the MDRD formula and measured GFR (51CrEDTA clearance) was –12.4 ml/min/1.73 m2 (P<0.001) (Figure 4). The performance of an equation largely depends on its precision, and SD of the mean difference was used to characterize the precision of each equation. It was 22.09 and 13.01 ml/min/1.73 m2 for C&G and MDRD formulas, respectively. The SD was significantly smaller for the MDRD formula (P<0.001).


Figure 1
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  		Fig. 1. Linear regression plots between 51CrEDTA clearance and reciprocal of serum creatinine (A) for all included patients (R = 0.628; P<0.0001), and (B) separately for men (R = 0.727; P<0.0001) and (C) women (R = 0.699; P<0.0001).

 

Figure 2
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  		Fig. 2. Linear regression plots between 51CrEDTA clearance and reciprocal of serum cystatin C (A) for all included patients (R = 0.753; P<0.0001), and (B) separately for men (R = 0.732; P<0.0001) and (C) women (R = 0.793; P<0.0001). *Calculated creatinine clearance from the C&G formula. **Calculated creatinine clearance from the MDRD formula.

 

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  		Table 1. Linear regression statistics for calculated creatinine clearance from C&G and MDRD formula

 

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  		Table 2. Diagnostic accuracy (area under the ROC curves, sensitivity and specificity) at cut-off value for GFR 60 ml/min/1.73 m2 of serum cystatin C, serum creatinine, calculated clearance from the C&G and MDRD formulas. The GFR determined with 51CrEDTA was used as the gold standard

 

Figure 3
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  		Fig. 3. ROC curve analysis of diagnostic accuracy of serum cystatin C, serum creatinine, calculated clearance from C&G and the MDRD formulas. The GFR determined with 51CrEDTA was used as the gold standard and cut-off value was set at 60 ml/min/1.73 m2.

 

Figure 4
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  		Fig. 4. Bland and Altman [14] plot for differences between estimated GFR and measured GFR. On the x-axis, the average GFR is given and on the y-axis the difference in millilitre per minute per 1.73 m2 between the estimated GFR, derived from (A) C&G and (B) MDRD formula is given. The mean difference and the 1.96 SD limits are plotted.

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Kidney failure due to CKD is preceded by a stage of variable length during which GFR decreases. Despite all its disadvantages, serum creatinine concentration is still widely used for GFR estimation, as it is simple and cheap. Recently, serum cystatin C was proposed as a new endogenous marker of GFR. The results of our study indicate that serum cystatin C is a reliable marker of GFR in patients with mild to moderate impairment of kidney function (stages 2–3 of CKD; GFR 30–89 ml/min/1.73 m2). In 164 patients with CKD stages 2–3, the correlation between ‘gold standard’ 51CrEDTA clearance and serum cystatin C was better than the correlation between 51CrEDTA clearance and serum creatinine and also than the reciprocal of serum creatinine. There was no difference between genders considering the values of serum cystatin C concentration and, as expected, the values of serum creatinine concentration were statistically significantly higher in men. The current guidelines emphasize the need to assess kidney function using predictive equations rather than just serum creatinine; the most widely used are the C&G and MDRD formulas [1]. In our study, serum cystatin C correlated better with 51CrEDTA clearance than creatinine clearance calculated from the C&G and MDRD formulas. The study of Froissart et al. [4] showed that C&G and MDRD formulas largely lack precision and the greatest lack of precision was observed for subjects who had measured GFR ≥60 ml/min/1.73 m2. Only ~70% of patients were classified in the proper category when using these formulas, which clearly highlights their limitations [4]. Approximately 20% of patients with a measured GFR ≥60 ml/min/1.73 m2 were classified as having stage 3 CKD, which could lead to unnecessary assessment of CKD-related complications [4]. Another important problem is that it is not always clear from the studies which creatinine method was used in predictive equations [15]. C&G and MDRD formulas for calculating GFR correlated in the study of Wuyts et al. [15] closely with 51CrEDTA clearance when calculated with the creatinine results from high performance liquid chromatography (HPLC), enzymatic and compensated Jaffé methods. Results obtained with the same formulas were lower than 51CrEDTA clearance when the uncompensated Jaffé method was used [15]. Clinicians are often unaware of this problem. When kidney function is assessed using prediction equations, it is important which creatinine method is used, and if the uncompensated Jaffé method is used, recalculation should be done before applying these formulas. In our study, the compensated Jaffé method was used, which is comparable to the enzymatic method [12].

All the patients in the study were analysed and according to our results, including the large number of well-defined patients with CKD stages 2–3 (GFR 30–89 ml/min/1.73 m2), serum cystatin C had a significantly higher diagnostic accuracy than serum creatinine and creatinine clearance calculated from the C&G formula. When men and women were analysed separately, higher diagnostic accuracy was found only in female patients. No difference in diagnostic accuracy between serum cystatin C and creatinine clearance, calculated from the MDRD formula was found in the category of all patients included in the study nor in the one seperated by gender. Creatinine clearance calculated from the MDRD formula had significantly higher diagnostic accuracy than creatinine clearance calculated from the C&G formula and the result was similar in all patients and both genders. The Bland and Altman analysis showed a mean difference between calculated GFR from the MDRD formula and measured GFR (51CrEDTA clearance) of –12.4 ml/min/1.73 m2, and the difference was statistically significant. The mean difference between calculated GFR from the C&G formula and measured GFR (51CrEDTA clearance) was only 0.6 ml/min/1.73 m2. Since we used a plasma clearance method to measure GFR, our measurements of 51CrEDTA clearance could be overestimated compared with true GFR. The Bland and Altman [14] analysis also showed that the MDRD formula was more precise than the C&G formula. According to our results, when assessing kidney function using predictive equations, the MDRD formula should be used in CKD stages 2–3 patients. Also, in the large studies of Froissart et al. [4] and Poggio et al. [5], the calculated clearance from the MDRD formula was more accurate and precise than the calculated clearance from the C&G formula for normal and reduced levels of kidney function with the exception of older women with GFR <60 ml/min/1.73 m2.

Available data considering serum cystatin C as a marker of GFR in patients with mild to moderate impairment of kidney function, comparing serum cystatin C with serum creatinine and creatinine clearance calculated from the C&G and MDRD formulas, are few and contradictory and include only small numbers of patients [2,7,16,17]. In a study by Hoek et al. [16], serum cystatin C and creatinine clearance calculated from the C&G formula gave better diagnostic accuracy than serum creatinine, but no significant difference in diagnostic accuracy between serum cystatin C and creatinine clearance calculated from the C&G formula was found. In this study, only 123 patients with different stages of CKD (GFR from 12.3 to 157 ml/min/1.73 m2) were included [16]. Kyhse-Andersen et al. [17] included 27 healthy controls and 24 patients with reduced GFR (<80 ml/min/1.73 m2) and found a significantly better correlation of serum cystatin C to GFR determined by clearance of iohexol than serum creatinine, and revealed that the diagnostic accuracy of serum cystatin C for reduced GFR was superior to that of serum creatinine [17]. In a study by Donadio et al. [2], no significant difference in the overall diagnostic accuracy of serum cystatin C and that of serum creatinine was found. No difference in diagnostic accuracy was found even when a cut-off level of <60 ml/min/1.73 m2 was used. Only 47 patients were included at that cut-off level. Risch et al. [18] found a better correlation with GFR for cystatin C than for creatinine clearance calculated from the C&G formula in renal transplant patients. Reciprocal of serum cystatin C had a significantly higher diagnostic accuracy than reciprocal of serum creatinine, using a GFR cut-off of 60 ml/min/1.73 m2 [18]. Grubb et al. [19] found that the cystatin C-based formula had higher accuracy in predicting GFR than the C&G formula. Estimates that are based on levels of creatinine, in contrast to those on C&G and MDRD formulas, are accurate only when kidney function is abnormally low; cystatin C overcomes this limitation even when glomerular filtration is normal or elevated, as seen in patients with early kidney disease associated with diabetes [20].

In conclusion, CKD is an important public health problem and according to the current K/DOQI guidelines, patients are classified on the basis of GFR estimations. Our results indicate that serum cystatin C is a reliable marker of GFR in patients with mild to moderate impairment of kidney function. In our well-defined patients with CKD stages 2–3, serum cystatin C had higher diagnostic accuracy in distinguishing patients with mildly to moderately impaired kidney function than serum creatinine and calculated clearance from the C&G formula, but only in female patients. No difference in diagnostic accuracy was found between serum cystatin C and creatinine clearance calculated from the MDRD formula. Estimation of serum cystatin C is no longer technically difficult and in patients with mild to moderate impairment of kidney function, cystatin C could be used as a marker of GFR. In female patients, cystatin C should be used to minimize diagnostic errors, despite the fact that it is still more expensive than the estimation of serum creatinine concentration.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. National Kidney Foundation: K/DOQI Clinical practice guideline to define chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 [Suppl 1]: S1–S266[CrossRef][Web of Science][Medline]
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  3. Levey AS, Berg RL, Gassmann JJ, Hall PM, Walker WG. Creatinine filtration, secretion and excretion during progressive renal disease. Kidney Int 1989; 36 [Suppl 27]: S73–S80
  4. Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft–Gault equations for estimating renal function. J Am Soc Nephrol 2005; 16: 763–773[Abstract/Free Full Text]
  5. Poggio ED, Wang X, Greene T, Van Lente F, Hall PM. Performance of the modification of diet in renal disease and Cockcroft–Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 2005; 16: 459–466[Abstract/Free Full Text]
  6. Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of renal function: a review. Clin Chem Lab Med 1999; 37: 389–395[CrossRef][Web of Science][Medline]
  7. Coll E, Botey A, Alvarez L et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis 2000; 36: 29–34[Web of Science][Medline]
  8. Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabelled human cystatin C in the rat. Scand J Clin Lab Invest 1996; 56: 409–414[Web of Science][Medline]
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  10. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta analysis. Am J Kidney Dis 2002; 40: 221–226[CrossRef][Web of Science][Medline]
  11. Hojs R, Bevc S, Antolinc B, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in the elderly. Int J Clin Pharm 2004; 24: 49–54
  12. Mazzachi BC, Peake MJ, Ehrhardt V. Reference range and method comparison studies for enzymatic and Jaffé creatinine assay in plasma and serum and early morning urine. Clin Lab 2000; 46: 53–55[Medline]
  13. Blaufox MD, Aurell M, Bubeck B et al. Report of the radionuclides in nephrology committee on renal clearance. J Nucl Med 1996; 37: 1883–1890[Abstract/Free Full Text]
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  15. Wuyts B, Bernard D, Van den Noortgate N et al. Revaluation of formulas for predicting creatinine clearance in adults and children, using compensated creatinine methods. Clin Chem 2003; 49: 1011–1014[Free Full Text]
  16. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003; 18: 2024–2031[Abstract/Free Full Text]
  17. Kyhse-Andersen J, Schmidt C, Nordin G et al. Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. Clin Chem 1994; 40: 1921–1926[Abstract/Free Full Text]
  18. Risch L, Blumberg A, Huber A. Rapid and accurate assessment of glomerular filtration rate in patients with renal transplant using serum cystatin C. Nephrol Dial Transplant 1999; 14: 1991–1996[Abstract/Free Full Text]
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  20. Perkins BA, Nelson RG, Krolewski AS. Cystatin C and the risk of death. N Engl J Med 2005; 353: 842–844[Free Full Text]
Received for publication: 27. 9.05
Accepted in revised form: 7. 2.06


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