Cystatin C as a marker of GFR—history, indications, and future research

Clinical Biochemistry 38 (2005) 1 – 8

Review

Cystatin C as a marker of GFR—history, indications, and future research

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Guido Fillera,*, Arend Bfkenkampb, W. Hofmannc, Thierry Le Bricond, Cecı´lia Martı´nez-Bru´e, Anders Grubbf a

Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada b Department of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands c Department of Clinical Chemistry, Mu¨ nchen, Germany d Laboratoire de Biochimie A, Hoˆpital St-Louis, Vellefaux, 75010 Paris, France e Servei de Bioquimica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain f Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden Received 16 February 2004; accepted 13 September 2004 Available online 18 November 2004

Abstract Objective: To summarize recent knowledge on the small molecular weight protein cystatin C (cys-C) and its use as a marker of the glomerular filtration rate (GFR). Methods: A multinational expert meeting was held in April 2002 in Marburg, Germany. Contributors summarized their main findings. Conclusions: Cys-C is at least equal if not superior to serum creatinine as a marker of GFR. The independence from height, gender, age, and muscle mass is advantageous. Select patient groups such as children, the elderly, and patients with reduced muscle mass benefit in particular. D 2004 The Canadian Society of Clinical Chemists. All rights reserved. Keywords: Cystatin C; GFR; Creatinine

Contents Features of cys-C . . . . . . . . . . . . . . . . . . . . . What is cys-C and where is it produced? . . . . . . . Physicochemical properties of cys-C . . . . . . . . . . Factors altering cys-C production . . . . . . . . . . . Cys-C as a marker of GFR (glomerular filtration rate) . Cys-C in select patient groups. . . . . . . . . . . . . . . Cys-C in children and adolescents . . . . . . . . . . . Cys-C in the elderly . . . . . . . . . . . . . . . . . . Cys-C in pregnancy . . . . . . . . . . . . . . . . . . Cys-C in renal transplantation . . . . . . . . . . . . . Diagnostic performance of cys-C . . . . . . . . . . . . . Open questions and future work. . . . . . . . . . . . . . Cost aspects . . . . . . . . . . . . . . . . . . . . . . . .

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Proceedings of a multinational expert meeting, April 2002, Marburg, Germany. * Corresponding author. Fax: +1 613 738 3254. E-mail address: [email protected] (G. Filler).

0009-9120/$ - see front matter D 2004 The Canadian Society of Clinical Chemists. All rights reserved. doi:10.1016/j.clinbiochem.2004.09.025

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

besides those affecting the glomerular filtration rate (GFR), which is also compatible with a stable secretion of cys-C from most human tissues [15,16].

Features of cys-C What is cys-C and where is it produced? Cystatin C (cys-C) is a low molecular mass protein that was initially known as inter alia g-trace, post-g-globulin, and gamma-CSF. The amino acid sequence of the single polypeptide chain of human cys-C was determined in 1981 [1]. The protein did not display any significant homology with the sequences of any protein at that time. Today, we know that the amino acid sequence of cys-C was the first sequence of the cystatin superfamily to be determined [2]. Two years later, cys-C was identified as an inhibitor of cysteine proteases after discovering significant homology with the sequence of chicken cystatin—the proteins had a sequence identity of 44% [3–6]. Over the last two decades, 11 further human cysteine protease inhibitors have been identified, which display strong sequence homologies to cys-C and chicken cystatin and consequently, belong to the human cystatin superfamily. The human cystatin family therefore presently comprises 12 proteins (Table 1). Cys-C is unique among cystatins as it seems to be produced by all human nucleated cells. Immunochemical and Northern blot studies of human tissues and cell lines have shown that cys-C or its mRNA is present in all investigated cell types [7–10]. Likewise, investigations of the production of cys-C by human cell lines in culture have displayed that all cell lines investigated secrete cys-C [11– 13]. Determination of the structure of the human cys-C gene and its promoter has demonstrated that the gene is of the housekeeping type, which indicates a stable production rate of cys-C by most nucleated cell types [7]. The presence of a hydrophobic leader sequence in pre-cys-C strongly indicates that the protein is normally secreted [7,14]. Studies of the serum level of cys-C in large patient cohorts have failed to correlate the serum level to any pathophysiological state

Physicochemical properties of cys-C Cys-C has a molecular mass of 13,343 Da, as determined both by mass spectrometry and by calculation from the amino acid sequence of its single polypeptide chain [15,17]. About 50% of cys-C carries a hydroxylated proline residue at position three, and the molecular mass of hydroxylated cys-C is thus 13,359 Da. The crystal structure of cys-C is known [18] and the canonical features of cys-C and chicken cystatin include a long a1 helix running across a large, five-stranded antiparallel h-sheet [19]. Both cys-C and chicken cystatin have ellipsoid shapes with axes of about 30 and 45 2 [19]. The isoelectric point of cys-C is 9.3 and the protein is thus positively charged in virtually all body fluids [15]. The physicochemical properties of cys-C are given in Table 2. Physiological concentrations in various body fluids are given in Table 3. Factors altering cys-C production Obviously, it is important to verify that cys-C production is constant. To date, only few circumstances have been identified that have an impact on the production of cys-C. Very large doses of glucocorticoids have been described to increase the production of cys-C [20,21], whereas low and medium doses of glucocorticoids do not seem to alter the production of cys-C [22]. Thyroid dysfunction also has a major impact on cys-C levels [23]. This applies even for mild thyroid dysfunction [24]. Therefore, thyroid function has to be considered when cys-C is used as a marker of kidney function. In contrast to creatinine concentrations, cys-C levels are lower in the hypothyroid and higher in the hyperthyroid state as compared with the euthyroid state. Cys-C as a marker of GFR (glomerular filtration rate)

Table 1 The human cystatin superfamily Family 1

Family 2

Family 3

Intracellular cystatins

Extracellular and/or transcellular cystatins Cystatin C Cystatin D Cystatin E Cystatin F Cystatin G Cystatin S Cystatin SA Cystatin SN

Intravascular cystatins

Cystatin A Cystatin B

5 6

LMW-kininogen HMW-kininogen

Small molecular weight proteins have long been proposed as markers of GFR as they are normally almost freely filtered through the normal glomerular membrane [25]. In a normally functioning kidney, these small molecular weight proteins should then be almost completely reabsorbed and degraded by proximal tubular cells. Indeed, studies of the handling of human cys-C in the rat have shown that the plasma renal clearance of cys-C is 94% of the renal clearance of the generally used GFR marker 51Cr-EDTA and that cys-C is thus practically freely filtered in the

G. Filler et al. / Clinical Biochemistry 38 (2005) 1–8 Table 2 Physicochemical properties of human cystatin C Polypeptide chains: one, with 120 amino acid residues Glycosylation: none Molecular mass: 13,343 Da (nonhydroxylated); 13,359 Da (hydroxylated proline residue at position 3) Isoelectric point: 9.3 Electrophoretic mobility: g3 (agarose gel electrophoresis at pH 8.6) Extinction coefficient: 1.22  104 (mol 1 L cm 1) = 9.1 (280 nm, 1%, 1 cm) Amino acid sequence SSPGK PPRLV GGPMD ASVEE EGVRR ALDFA VGEYN KASND MYHSR ALQVV RARKQ IVAGV NYFLD VELGR TTCTK TQPNL DNCPF HDQPH LKRKA FCSFQ IYAVP WQGTM TLSKS TCQDA Disulfide bonds: between residues 73 and 83 and between residues 97 and 117 Gene location: chromosome 20 at p.11.2 DNA sequence: the nucleotide sequence data are available from the EMBL, GenBank, and DDBJ Nucleotide Sequence Databases under the accession number X52255 Half-life: about 20 min, experimentally determined for human cystatin C in rat plasma. (The similarity in distribution volume and renal clearance between human cystatin C and acknowledged markers of human glomerular filtration, that is, iohexol and 51Cr-EDTA, suggests that the substances are eliminated at the same rate in humans with a half life of approximately 2 h in individuals with normal renal function.)

glomeruli [26]. At least 99% of the filtered cys-C is degraded in tubular cells. When the GFR of a set of rats was variably lowered by constricting their aortas above the renal arteries, the renal plasma clearance of cys-C correlated strongly with that of 51Cr-EDTA with a linear regression coefficient of 0.99 and with the y-intercept not being statistically different from 0 [27]. This observation clearly implied an insignificant peritubular uptake of cys-C. Immunohistochemical and Northern blot studies of human kidneys have also strongly indicated that human cys-C is normally degraded by proximal tubular cells after its passage through the glomerular membrane [10]. Given these characteristics, together with its constant production, cys-C would be an ideal marker of GFR (Table 3). Early investigations demonstrated that serum cys-C was indeed a marker of GFR, at least as good as serum creatinine in the populations investigated [28,29]. These studies also showed that the serum cys-C level was a better GFR marker than the serum levels of the other low molecular mass proteins investigated, such as h2-microglobulin, retinol binding protein, and complement factor D [22]. However, in these early studies, the cys-C concentration was determined by enzyme-amplified single radial immunodiffusion. This procedure is slow, requiring at least 10–20 h, and has a relatively high coefficient of variation (about 10%) that decreases the usefulness of the obtained serum cys-C value as a GFR marker in the clinical routine. The subsequent development of automated and rapid particleenhanced immunoturbidimetric and immunonephelometric methods, which are rapid as well as more precise [30–34], has allowed large-scale use of serum cys-C as a clinically

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useful GFR marker. The FDA recently approved one of these assays [30].

Cys-C in select patient groups Select patient groups, whose muscle mass is either reduced or undergoes rapid changes, may benefit in particular from the development of a new marker of GFR. This is true for children and the elderly. Another target group includes patients for whom precise determination of GFR is critical, such as renal transplant recipients. It is therefore not surprising that many studies focus on these patient cohorts. Cys-C in children and adolescents Particularly in children, gold standard methods for the determination of GFR such as inulin clearance are expensive, cumbersome, and invasive, as they require catheterization for timed urine collection. Therefore, a surrogate marker of GFR is needed. The most commonly used laboratory parameter to estimate GFR is serum creatinine. The limitations of serum creatinine as an ideal marker of GFR in children and adolescents are well established. Creatinine production depends on muscle mass [35], which increases with growth and pubertal development, especially in boys. Therefore, the reference range for serum creatinine increases with age until the end of puberty and has to be adjusted for gender from puberty onwards. Furthermore, the error produced by renal tubular creatinine secretion and nonrenal elimination is particularly important for children because of their physiologically low serum creatinine [36] and low muscle mass [37]. Under-recognition of renal dysfunction, especially by physicians not accustomed to the physiology of creatinine, is common [38–40]. Several formulae were developed to address these limitations [41,42]. They allow the estimation of GFR from height/creatinine ratio. A constant k is needed to reflect body composition [43] and differing constants apply for gender and certain age groups [42]. These formulae fail in patients with altered body composition or reduced muscle mass, such as patients with spina bifida, neuromuscular disease, anorexia nervosa, or liver cirrhosis [44].

Table 3 Normal concentrations of human cystatin-c in body fluids Concentrations in body fluids of healthy adults (mg/L; mean and range) Blood plasma: 0.96; 0.57–1.79 Cerebrospinal fluid: 5.8; 3.2–12.5 Urine: 0.095; 0.033–0.29 Saliva: 1.8; 0.36–4.8 Seminal plasma: 51.0; 41.2–61.8 Amniotic fluid: 1.0; 0.8–1.4 Tears: 2.4; 1.3–7.4 Milk: 3.4; 2.2–3.9

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Unlike serum creatinine, the serum concentration of cys-C remains constant from around 1 to 50 years of age [39– 41,45–47]. Many studies established pediatric reference ranges. Upper reference values lie between 0.95 [41] and 1.27 mg/l [28] for Dade Behring’s particle-enhanced immunonephelometric assay (PENIA), and around 1.38 mg/l for DAKO’s immunoturbidimetric assay (PETIA) [48]. The reference limits were reviewed in Ref. [49]. In this review, the reference values for cys-C obtained in a carefully selected population were 0.75 F 0.089 mg/l for children aged 4–19 years, 0.74 F 0.100 mg/l for males and 0.65 F 0.085 mg/l for females (aged 20–59 years), and 0.83 F 0.103 mg/l for older individuals (greater than or equal to 60 years). In the first year of life, renal function matures physiologically. Accordingly, much higher cys-C values, up to 2.8 mg/l, were found at birth. These are subject to a rapid decline after birth reflecting maturation of kidney function [39,40,47]. There appears to be no diaplacental transfer of cys-C [50,51]. Unlike serum creatinine, cys-C can thus be used to assess the GFR of the newborn and even the fetus. Data in utero [51]—as well as postpartum [52,53]—indicate that serum cys-C is independent of gestational age facilitating its use in premature infants. Typically, studies test for the correlation of GFR and the reciprocal of surrogate markers to assess the feasibility of using them as a surrogate marker. With the exception of one study [54], the reciprocal of cys-C correlates better with a gold standard GFR measurement than serum creatinine [55–58]. Cys-C as a marker of GFR was found to be independent of body composition [59–61]. It has been shown recently that cys-C is the only marker of GFR that is reliable in patients with spina bifida or spinal cord injury in whom creatinine determinations are notoriously inaccurate [62,63]. Cys-C in the elderly Many of the limitations that apply to children are also valid for elderly people, especially for small patients with a low muscle mass. The limitations of serum creatinine have been stressed for this population [64]. Again, creatinine-based formulae such as the Cockcroft–Gault and Modification of Diet in Renal Disease (MDRD) have been developed to overcome the problem. However, cys-C was shown to be a superior marker for the early detection of renal impairment [65,66]. Cys-C in pregnancy Assessment of renal function in pregnancy remains a challenge. It is known that the GFR as measured by inulin clearance [67] increases early in pregnancy. This is thought to be secondary to increased renal reserve [68]. In an outpatient setting, creatinine clearance actually tends to go down in the third trimester [69], while other studies

suggest that the supranormal creatinine clearance remains stable throughout the later part of pregnancy [70,71]. Few studies have looked at cys-C in pregnancy. Cataldi et al. [50] found higher cys-C concentrations in pregnant women at term when compared to reference values obtained from healthy subjects. As altered renal function is an essential component of the pathophysiological process in preeclampsia and as early diagnosis is important, cys-C was studied in this condition. Using receiver operating characteristic (ROC) analysis, Strevens and Wide-Swensson [72] showed a better diagnostic performance when compared to serum creatinine. Using iohexol clearances as a gold standard GFR, the same group also showed that the correlation between cys-C and GFR was set at different levels for pregnant and nonpregnant women [73]. It was later shown that cys-C rises progressively from the second to the third trimester in uneventful pregnancy [74]. This observation might reflect the previous observation that the fractional clearance of substances with a molecular mass similar to that of cys-C decreases during the last trimester [75] but may also suggest unconstant production during pregnancy. However, cys-C was shown as a marker of endotheliosis [76]. More work is required to establish whether the measurement of cys-C will have a clinical role in the assessment for renal disease in pregnancy. Cys-C in renal transplantation Kidney transplantation is the option of choice to treat terminal renal disease in adults and children. Close monitoring of graft function is mandatory for the detection of allograft rejection (acute and chronic) and the monitoring of drug nephrotoxicity. In practice, the determination of blood creatinine (in plasma or serum) is the first line parameter to estimate GFR due to low cost, full automation (24 h availability, approximately 10 min for a result), low intra-individuality, and experience from clinicians (especially nephrologists). Clinical data using cys-C for the follow-up of renal transplant patients remain scarce. Since the first publication in 1998 [77], several original clinical papers have addressed the question of the use of cys-C in kidney transplantation. Higher intra-individual variability of cys-C concentrations when compared to serum creatinine has been reported in kidney transplant recipients [78], questioning its use for individual follow-up. Two other studies—limited to the immediate postoperative phase [79,80]—did not confirm that difference between creatinine and cys-C intra-individual variability in children. In a careful study comparing gold standard reference GFR determination with cys-C in stable recipients performed at distance from surgery, a better correlation was found between cys-C and GFR than for creatinine (using the reciprocal of their concentration): r = 0.879 vs. r = 0.784 [81]. While several other studies gave varying results, the largest study to date with 110 patients [82] demonstrated

G. Filler et al. / Clinical Biochemistry 38 (2005) 1–8

that serum cys-C accurately reflects creatinine clearance over the entire range of transplant function and is as efficacious as serum creatinine to detect reduced creatinine clearance in renal transplant recipients. Many questions remain unanswered; for instance, postoperatively, cys-C decreased more rapidly than creatinine following surgery with a switch around day 4. After this, GFR based on creatinine was then higher than cys-C until discharge [79]. Hermida et al. [83] and Bfkenkamp et al. [79] confirmed this phenomenon even if the switch occurred earlier in this pediatric study, while the underlying mechanisms are not understood. At the present time, the prognostic value (if any) of the postoperative cys-C kinetic following allograft transplantation is unknown.

Diagnostic performance of cys-C The independence from height, age, gender, and body composition as well as acute phase reactions, with renal function being the main determinant of cys-C serum concentration, makes cys-C an interesting candidate surrogate marker of GFR. Many studies tested for agreement of a cys-C-derived GFR and gold standard methods using Bland–Altman analysis [84]. Most studies found no systematic deviation but a scatter of F40% (F2 standard deviations) between an exogenous clearance measurement and the GFR calculated from serum cys-C concentrations [59,85]. While definitively not worse than other creatinine-based formulas as a surrogate marker of GFR, the relatively higher intra-individual variability of cys-C [86] has to be considered as a limitation. The early results of Keevil et al. [86] are probably due to the fact that they used the first boldQ DAKO method that was disturbed by turbid samples and included postprandial samples in their investigation. Later studies, using methods not disturbed by turbidimetry, have indicated that the intra-individual variability of cysC and creatinine is similar [87]. The diagnostic performance of cys-C in comparison with serum creatinine was recently analyzed in a metaanalysis on 46 studies, both in adults and children [16]. The pooled data analysis compared correlation coefficients between GFR and the reciprocals of serum creatinine and cys-C in 3703 individuals and found significantly better correlations for cys-C (mean r = 0.816 [95% confidence interval: 0.804–0.826] vs. mean r = 0.742 [95% confidence interval: 0.726–0.758]). ROC plots were available for a pooled sample size of 997 individuals, again showing a significantly better area under the [ROC] curve (mean = 0.926 [95% confidence interval: 0.892–0.960] vs. mean r = 0.837 [95% confidence interval: 0.796–0.878]). This metaanalysis suggests that cys-C is superior to serum creatinine for the detection of impaired GFR in crosssectional studies.

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Open questions and future work Meta-analysis evidence was produced on the superiority of cys-C for the detection of impaired GFR in crosssectional studies, even when using creatinine formulae based on height, age, gender, and so forth. Cys-C is therefore a useful screening tool to answer the question whether renal function is normal in a given subject. However, significantly more work is required to address the conflicting information about the higher intra-patient variability in longitudinal studies when compared to serum creatinine. Few studies have analyzed intra-patient variability, and they were conducted predominantly in adult renal transplant recipients. Substantially more work is required in other patient groups. The significance of hormonal influences, such as hyperthyroidism or pregnancy, requires further exploration before cys-C can be considered as a replacement test for serum creatinine. And while acute phase reactions and altered body composition appear to be independent for the production of cys-C, the influence of drugs (corticosteroids, cyclosporine, and others) requires further evaluation. Finally, more work is required to evaluate the usefulness of cys-C as a marker of the adequacy of dialysis therapy [88,89].

Cost aspects Regarding cost/practicability, both creatinine and cys-C (e.g., using the BN ProSpecR system platform) are both easily and rapidly determined. Currently, the Dade Behring N Latex cys-C assay is the only assay that has FDA approval. Creatinine is about $0.25 while cys-C is approximately $3.00 US. However, a 51Cr-EDTA or 99Tc-DTPA clearance study is in the $50.00 US range, and is technically difficult, results in radiation exposure, and requires a halfday hospitalization. The costs are based on ordering costs for individual assays in Ontario; the quotation for the imaging study is the current Ontario Health Insurance Plan (OHIP) rate.

Conclusions Cys-C is a fascinating novel marker of GFR that bears certain advantages over the most widely used surrogate marker of GFR: serum creatinine. There is high-level evidence that the diagnostic sensitivity for the detection of mildly impaired GFR is superior [16]. The independence from height, gender, age, and muscle mass is advantageous. Select patient groups such as children, the elderly, and patients with reduced muscle mass benefit in particular. The usefulness of cys-C as a marker of GFR in pregnancy may be doubtful, while the same marker serves as an interesting tool for the early detection of preeclampsia. In kidney

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transplantation, it is still unclear if cys-C offers significant advantages over creatinine (and derived GFR estimates) both for the short-term and long-term management of allograft function.

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