Non-invasive estimation of glomerular filtration rate (gfr). the lund model: simultaneous use of cystatin c- and creatinine-based gfr-prediction equations, clinical data and an internal quality check

Scandinavian Journal of Clinical & Laboratory Investigation, 2010; 70: 65–70 INVITED REVIEW
Non-invasive estimation of glomerular fi ltration rate (GFR).
The Lund model: Simultaneous use of cystatin C- and
creatinine-based GFR-prediction equations, clinical
data and an internal quality check

Department of Clinical Chemistry, University Hospital, Lund, Sweden Abstract
Knowledge of glomerular fi ltration rate (GFR) is required to detect and follow impairment of renal function, to allow
correct dosage of drugs cleared by the kidneys, and for the use of nephrotoxic contrast media. Correct determination of
GFR requires invasive techniques, which are expensive, slow and not risk-free. Therefore, GFR-prediction equations based
solely upon cystatin C or creatinine and anthropometric data or upon cystatin C, creatinine and anthropometric data
have been developed. The combined prediction equations display the best diagnostic performance, but in several easily
identifi able clinical situations (e.g. abnormal muscle mass, treatment with large doses of glucocorticoids) prediction equa-
tions based upon either cystatin C or creatinine are better than the combined equations. In Lund, where cystatin C has
been used as a GFR-marker in the clinical routine since 1994, a strategy based upon this knowledge has therefore been
developed. This comprises simultaneous use of a cystatin C-based and a creatinine-based GFR-prediction equation. If the
GFRs predicted agree, the mean value is used as a reliable GFR-estimate. If the GFRs predicted do not agree, clinical data
is evaluated to identify reasons for not using one of the two prediction equations and the GFR predicted by the other one
is used. If no reasons for the difference in predicted GFRs are found, an invasive gold standard determination of GFR is
performed. If the GFRs predicted agree for a patient, the creatinine value is reliably connected to a specifi c GFR and can be used to follow changes in GFR of that patient. Key Words: Kidney function tests , estimation of glomerular fi ltration rate , creatinine , cystatin C , renal failure
particularly creatinine, have therefore been used as Knowledge of glomerular fi ltration rate (GFR) is markers for GFR for almost a century. But it has required to detect and follow impairment of renal become evident that the creatinine level alone is far function, to allow correct dosage of drugs cleared by from ideal as a GFR marker because it is signifi cantly Scand J Clin Lab Invest Downloaded from by University of Lund the kidneys and for the use of potentially nephrotoxic infl uenced not only by GFR but also by muscle mass, radiographic contrast media. GFR in humans cannot diet, gender, age, drugs and tubular secretion [1]. be measured directly and invasive techniques based Cystatin C was fi rst suggested as a new marker for on measuring the plasma or renal clearance rate of GFR in 1979, when it was observed that the plasma injected substances (e.g. inulin, 51Cr-EDTA, iohexol, level of cystatin C was up to 13 times higher in patients on haemodialysis than in healthy persons [2]. One of the cetic acid) that are exclusively excreted via glomerular methods developed in 1979 for determination of the fi ltration are therefore required for the correct mea- cystatin C level in body fl uids was enzyme-amplifi ed surement of GFR. However, these so called gold single radial immunodiffusion [2]. Although this pro- standard techniques cannot be generally applied cedure was slow and had a coeffi cient of variation of because they are labour-intensive, expensive and not 11%, it was useful for identifi cation of cystatin C as a entirely free of risk for the patient. The plasma or GFR-marker at least as good as creatinine, since the serum concentrations of endogenous substances, correlation coeffi cients for the relation between the Correspondence: Anders Grubb, Department of Clinical Chemistry, University Hospital, SE-22185 Lund, Sweden. Tel: ϩ4646173964. Fax: ϩ4646130064or ϩ4646189114. E-mail: or (Received 4 January 2010; accepted 4 January 2010) ISSN 0036-5513 print/ISSN 1502-7686 online 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/00365511003642535 serum levels of cystatin C and GFR, determined by a GFR-prediction equations, e.g. the MDRD- and gold standard method (plasma clearance of 51Cr- CKD-EPI-equations [35–38], implicitly use the EDTA), were somewhat higher than that between mean muscle mass of a person of a specifi ed age, sex creatinine and GFR [3,4]. However, development of and ethnic origin in the population employed to automated, rapid and precise methods for determina- derive the equation, to compensate for the muscle tion of the serum or plasma level of cystatin C was required for the use of cystatin C as a marker for GFR prediction of GFR. If a person’s muscle mass in the clinical routine. The fi rst method of this type, a deviates from the mean of that of persons of his/her particle-enhanced immunoturbidimetric method, was age, sex and ethnic origin in the population, the developed in 1994 [5] and applied for determination GFR-prediction equation will not be accurate for of the serum cystatin C levels in a cohort of 51 patients that person. This is an important reason for with GFR measured by a gold standard procedure. the remaining imprecision in the creatinine-based ROC curve analysis demonstrated that in this cohort GFR-prediction equations. It also explains why of patients, serum cystatin C had a signifi cantly better different creatinine-based equations are required for diagnostic performance than serum creatinine [5]. maximal diagnostic performance in different popula- Since then, several automated, rapid and precise meth- tions of individuals, as the relation between muscle ods for determination of cystatin C have been devel- mass, age, sex and ethnicity differs between different oped [6–12] and the information on cystatin C as a populations. For example, the MDRD-equation GFR-marker has substantially increased. Entering ‘cys- generally underestimates the GFR of healthy people tatin C AND (glomerular OR renal)’ in the search fi eld by 29% [39] and its application in a Japanese popu- of in February 2010 lation requires a Japanese-specifi c coeffi cient of 0.763 [40]. Nevertheless, in many clinical situations The main advantage of cystatin C compared to the creatinine-based GFR-prediction equations esti- creatinine as a GFR-marker is that it is less dependent mate GFR at least as well as cystatin C alone [41]. upon the body composition of a patient than creati- One drawback with presently available creatinine- nine. For example, while muscle mass strongly infl u- based GFR-prediction equations is that they usually ences creatinine, it does not, or only marginally, do not work for persons below 18 years of age, for affects cystatin C [13–15]. Muscle loss of a patient, which specialized prediction equations, e.g. those of e.g. by paralysis, immobilization or low mobility, Schwartz and Counahan-Barratt, have to be used involuntary or voluntary malnutrition (anorexia), [42,43]. However, recently a creatinine-based will strongly impair the use of creatinine as a GFR- GFR-prediction equation, the Lund-Malmö (LM) marker, but not that of cystatin C [16,17]. Muscle equation, which works for both adults and children, loss during aging reduces the production of creati- nine and therefore impairs the use of creatinine to Since the level of cystatin C is less dependent follow the decline of GFR with age. But the cystatin upon anthropometric data than that of creatinine, C production is not strongly infl uenced by muscle simpler cystatin C-based GFR-prediction equations mass and cystatin C will therefore increase with age of the type GFR ϭ A ϫ cystatin C –B can be used both in parallel with the decrease of GFR and therefore for adults and children [32,33,46–48]. Although cys- be more useful than creatinine to demonstrate the tatin C generally seems to be signifi cantly less depen- normal and abnormal decrease in GFR in the elderly dent upon anthropometric data than creatinine [49], Scand J Clin Lab Invest Downloaded from by University of Lund [18–28]. The muscle mass of children up to around this must be verifi ed for patient and ethnic groups the age of 18 years varies considerably; therefore, not yet studied. It should also be considered that whereas cystatin C alone and cystatin C-based GFR- required, whereas the cystatin C level is virtually con- prediction equations are less infl uenced by variation stant from 1 year, allowing uniform reference values in muscle mass than creatinine alone and creatinine- based GFR-prediction equations, the usefulness of cystatin C-based prediction equations are impaired in the same way as cystatin C alone by moderate and high doses of glucocorticoids which increase the Creatinine- and cystatin C-based
GFR-prediction equations
A considerable number of creatinine- or cystatin Since creatinine alone has clear drawbacks as a C-based GFR-prediction equations have been GFR-marker, it is widely considered that it should described [33–49]. The reasons for the present be replaced by GFR-prediction equations based not high number of equations are the use of different only upon creatinine, but also upon anthropometric calibrators, the use of non-accurate methods for and/or demographic data such as sex, age and ethnic- determinations of creatinine or cystatin C, the use of ity, to compensate for the infl uence of muscle mass different patient or ethnic populations and the use of on the creatinine level [34]. Most of the well-founded, different mathematical models to generate the pre- generally used and recommended creatinine-based diction equations. These factors must be carefully The Lund model for estimation of GFR 67 90–91% of which are within Ϯ 30% of GFR mea-sured by gold standard methods is close to what is theoretically attainable. It should, in addition, be considered that in evaluations of GFR-prediction equations, it is generally, but erroneously, assumed that the imprecision of the gold standard procedure used is 0%. This means that the calculated percentage of estimated GFR-values between Ϯ 30% of ‘true’ GFR is decreased because of the actual imprecision of the gold standard procedure. Figure 1. Age-related predictions of glomerular fi ltration rate The Lund model: Simultaneous use of
(mL/min/1.73 m 2) at a constant creatinine level of 80 μmol/L for cystatin C- and creatinine-based GFR-
a female using the Lund-Malmö (LM) [44], the MDRD [37] or the Counahan-Barratt equations [43,44]. The mean heights prediction equations, clinical data and
of Swedish children of different ages [63] were used for the an internal quality check
Although GFR-prediction equations based upon both cystatin C and creatinine clearly seem to have considered before a GFR-prediction equation is better diagnostic performance than prediction equa- selected for use in a particular patient population. tions based upon only one of these GFR-markers, For example, when a prediction equation, based such combined equations are not optimal in all upon a specifi c cystatin C calibrator and determina- clinical situations. To give some examples: in a patient tion method, is used to estimate GFR from the cys- suffering from paralysis with very low muscle mass, tatin C levels produced using another cystatin C the combined prediction equation will be less reliable calibrator and determination method, large errors in than a prediction equation based on cystatin C alone; the resulting GFR-estimates may result, even for in a patient treated with high doses of glucocorti- similar patient populations. One way of reducing the coids, the combined prediction equation will be less problems associated with the selection of a suitable reliable than a prediction equation using creatinine GFR-prediction equation is to produce international alone and anthropometric data. Thus, a strategy for calibrators for creatinine and cystatin C and use GFR-estimation based upon automatic use of a com- them, not only to secure the use of standardized bined prediction equation using both creatinine and calibrators in different methods, but also to develop cystatin C would consequentially have worse diag- and secure accurate methods for both cytatin C and nostic performance than a strategy in which both a creatinine. The use of validated international calibra- cystatin C-based and a creatinine-based prediction tors and accurate methods for determination of cre- equation are used, concomitantly taking clinical data atinine and cystatin C will decrease the number of validated equations and simplify the selection of an In Lund, where cystatin C has been available for equation suitable for a specifi c patient population. clinical use since 1994 [5], the following strategy for An international calibrator for creatinine is already estimation of GFR has been developed [61]. It is Scand J Clin Lab Invest Downloaded from by University of Lund available [37] and work is in progress to produce one based on three sources of information: the plasma levels of cystatin C and creatinine, respectively, as Although some creatinine- or cystatin C-based well as knowledge of the clinical context. Age and GFR-prediction equations produce estimated GFR- gender of the patient is always available, since they values 80–85% of which are between Ϯ 30% of GFR can be inferred from the unique identity number measured by invasive gold standard methods in some (Swedish personal registration number) used to studies, the highest percentages of estimated GFR- identify all patients. Relative GFR (ml/min/1.73m 2) values between Ϯ 30% of measured GFR-values are is estimated both by a prediction equation based obtained using GFR-prediction equations based upon cystatin C alone as well as by a prediction equa- upon both cystatin C and creatinine [41,49, 56–60]. tion based upon creatinine alone and anthropometric Such equations might produce estimated GFR- data. The two estimates are compared and, if they values 90–91% of which are between Ϯ 30% of GFR are in agreement within specifi ed limits, the arithme- measured by gold standard methods [41,59]. The tic mean of the two estimates is used. Diagnostically imprecision of all gold standard procedures means the arithmetic mean of the two estimates has been that even if a gold standard procedure is performed shown to perform at least as well as more complex twice within a short interval on patients with stable ways of combining the two estimates [59]. The spec- kidney function, less than 100% of the second deter- ifi ed limits for agreement between the two estimates mination will be within Ϯ 30% of the fi rst. Thus, a can either be applied automatically or the physician GFR-prediction equation producing GFR-values can stipulate what level of agreement is required for the specifi c patient under study. A higher degree of References
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