Delanghe, Joris

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Nephrol Dial Transplant (2009) 24: 714–716doi: 10.1093/ndt/gfn306Advance Access publication 29 May 2008How to estimate GFR in childrenJoris R. DelangheDepartment of Clinical Chemistry, Ghent University Hospital, Gent, BelgiumKeywords: creatinine; cystatin C; glomerular filtrationrate; standardizationIntroductionThe reference method to determine glomerular filtrationrate (GFR) in children is the inulin clearance. Similarly,Cr51-EDTA, iohexol and iothalamate can be used as ex-ogenous GFR markers [1,2]. Exogenous markers are ex-pensive and rather impractical. Creatinine is by far themost commonly used biochemical marker of renal func-tion. The commonest principle for assaying creatinine isthe Jaffe reaction [3]. Since Jaffe only observed a complex-ation between picric acid and creatinine in alkaline environ-ment and never described an analytical method, variationamongst ‘Jaffe method’ recipes is broad [4]. The analyticalbias of current creatinine methods (due to interference bypseudochromogens and calibration differences) is still dis-appointing: the compensated Jaffe method shows a smallpositive bias, whereas a major positive bias is observed forthe dry chemistry and the uncompensated Jaffe methods[5]. Interlaboratory variation for creatinine is still unac-ceptably high; recent studies have reported median methodgroup variation coefficients of 6.4% at a concentration of80 µmol/L [6]. Such variation leads to an unacceptable vari-ation in the estimation of kidney function in young childrenand infants. Equations to estimate GFR require knowledgeof the calibration of the serum creatinine assay [7].Restandardization of creatinineRecently, a new commutable serum creatinine referencematerial (NIST SRM 967) has become available. This ma-terial is value assigned with the gas chromatography iso-tope dilution mass spectrometry (GC-IDMS) and liquidchromatography isotope dilution mass spectrometry (LC-IDMS) reference measurement procedures. Implementingtraceability of serum creatinine assays to the new standardmaterial will lead to major changes in the clinical decision-Correspondence and offprint requests to: Joris R. Delanghe, De-partment of Clinical Chemistry, Ghent University Hospital, DePintelaan 185 (2P8), B-9000 Gent, Belgium. Fax: +32-9-332-4985; E-mail: joris.delanghe@ugent.bemaking criteria currently used for serum creatinine andcreatinine clearance [7].In the earliest manual and automated methods, serumcreatinine was assayed by the Jaffe reaction after depro-teinization or dialysis, eliminating the pseudo-chromogeneffect of proteins. Modern analysers use undiluted serumand plasma, making them prone to the so-called protein er-ror in the alkaline picrate reaction [8]. In the serum of adults,this effect produces a positive difference of ∼27 µmol/L(±0.3 mg/dL) creatinine compared with HPLC or enzy-matic methods [8]. Because urine contains relatively littleor no protein, the protein error affects only creatininedeterminations in serum or plasma. Therefore, creatinineclearance is underestimated when creatinine methods af-fected by protein error are used. For calculating GFR, thissystematic positive bias is greatly compensated by the over-estimation attributable to tubular secretion of creatinine,which is relatively more important in children [8].Serum or plasma creatinine values are often used for es-timating GFR [8]. For adults, the currently recommendedestimating equation has been developed from the Modifi-cation of Diet in Renal Disease (MDRD) Study [9]. Thecurrent variability in the calibration of serum creatinineassays introduces a source of error into GFR estimates. Inparticular, variability in creatinine calibration and measure-ment imprecision contributes to substantial uncertainty inestimating GFR in children, who usually have lower serumcreatinine concentrations than adults. The recent availabil-ity of the international NIST SRM 967 standard means animportant milestone in the improvement of GFR estimationin adults [10].Consequences of creatinine restandardizationFor adults, an improved GFR-estimating equation based onserum creatinine values traceable to IDMS reference mea-surement procedures has been presented [7]. Manufacturerscan restandardize their Jaffe creatinine assays using a so-called compensation, a mathematical correction that com-pensates for analytical non-specificity due to the proteinerror. Since children show lower reference ranges for totalprotein, this protein error is considerably smaller [11]. Inconsequence, use of restandardized Jaffe-type assays resultsin overcompensation when used in children or infants (oc-casionally even leading to negative values in children witha decreased muscle mass!). Enzymatic methods manage toC© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.orgNephrol Dial Transplant (2009) 24: Editorial Comments 715Table 1. Example of creatinine-based GFR estimation problems in a 4-year-old boy (height 100 cm)Analytical method Serumcreatinine(mg/dL)GFR-Schwartz(mL/min)GFR-Counahan(mL/min)Non-compensated Jaffe 0.71 77.5 60.6Compensated Jaffe (adapted to SRM967)0.41 134.1 105Enzymatic (adapted to SRM 967) 0.47 117 91measure the serum creatinine more correctly. Due to theelimination of analytical non-specificity, the lower enzy-matic creatinine result (when the result has not been ad-justed to Jaffe-like results) leads to markedly increased cre-atinine clearance and GFR values because of the increasedeffect of tubular secretion. Paradoxically, the analytical im-provement makes creatinine less suited as a GFR markerin paediatric medicine [11]. When creatinine clearance ismeasured in patients who have been administered cimeti-dine, the effect of tubular secretion can be corrected [12].However, this method cannot be used on a wide scale.The bias in serum creatinine concentration in the lowerrange is a major concern in paediatrics due to the muchlower reference ranges for serum or plasma creatinine ininfants and children [13,14]. For estimating GFR in chil-dren and infants, the Schwartz [15–17] and the Counahan–Barratt equations [18] are recommended. Both provide GFRestimates based on a constant multiplied by the child’sheight divided by the serum creatinine concentration. Thevalues for the constant used in both equations differ con-siderably: k = 38 (Counahan) versus k = 48.7 (Schwartz)[19]. Since these formulas have been validated 30 years ago(using Jaffe recipes that are no longer on the market), re-assessment of classical formulas for estimating creatinineclearance and GFR using modern assays is strongly recom-mended. Despite the major change in values caused by therecent standardization, so far no clinically validated adap-tations of creatinine-based formulas for estimating GFRin children have been published. It is clear that this willbe difficult; compensated Jaffe results will be less suitedthan enzymatic methods as a base for these calculations.Theoretically, the expression kL/(creatinine) (in which k isa constant and L the child’s length) could be replaced bykL/[(creatinine; IDMS calibrated) + non-specificity cor-rection] when using the new IDMS-calibrated assays. How-ever, this non-specificity correction shows a variation [8]that increases the uncertainty of the estimation. It is clearthat extreme care will have to be taken since coefficientswill depend on the method chosen. Table 1 illustrates theGFR estimation problems in children due to creatinine stan-dardization.Alternative markersSerum concentrations of low-molecular-weight marker pro-teins are primarily determined by GFR. Cystatin C (CysC) is a 13 kDa cysteine protease that is produced by allnucleated cells [13,20]. The gene is of the house-keepingtype, which is compatible with a stable production rateeven in the presence of inflammatory stimuli. As a GFRmarker in paediatric populations [21], serum Cys C lev-els generally show diagnostic superiority or equivalenceof serum Cys C versus serum creatinine. Especially in theblind range of creatinine, Cys C proves to be a superiormarker. Unlike creatinine, serum Cys C reflects renal func-tion in children independent of age, gender, height andbody composition [21]. Clinicians should be cognizant of anumber of caveats (upregulation in certain tumours, gluco-corticoid treatment, thyroid dysfunction) that can influenceCys C results [22,23]. Serum creatinine values are lower inmalnourished children and lead to overestimation of GFR,while Cys C levels are unaffected [24].In comparison with the Schwartz formula, Cys C-basedGFR estimates show significantly less bias and serve asa better estimate for GFR in children [25]. Internationalstandardization for Cys C by an International Federationof Clinical Chemistry (IFCC) working group is nearingcompletion. Beta trace protein (BTP) is a 23–29 kDa pro-tein, which has been introduced for the measurement ofkidney function in the creatinine-blind range [7,26]. Beta2-microglobulin has been advocated as a GFR marker [7],but its serum concentration can increase as an acute-phasereactant or as a tumour marker in lymphoproliferative dis-orders [7].Next stepsBetween-laboratory variation of Jaffe-based methods hasnot decreased over the last decade, despite technicalprogress [5]. Analytical bias in creatinine assays needs to bereduced and non-specificity bias should be improved and, ifnecessary, adapted to a paediatric serum matrix. The creati-nine standardization issue has major clinical consequencesthat are far beyond the significance of the parameter itself.Apart from the conventional calculation of the creatinineclearance, also the calculation of the clearance using de-rived formulas is a key element in the assessment of renalfunction and the dose calculation of many drugs [27]. Manyexisting drug dosage schemes have been based using poorlydescribed non-specific ‘Jaffe’ methods.When introducing revised serum creatinine calibrationtraceable to IDMS, laboratories will need to communicatewith paediatricians and pharmacists: serum creatinine ref-erence intervals will drop, calculations of estimated GFRused by pharmacists or other health care professionals toadjust drug dosages will be affected by the decreased crea-tinine values, measured and calculated creatinine clearancevalues and GFR values will increase, and their correspond-ing reference intervals will be different.In view of the difficulties in adapting creatinine assaysto the new calibrators in the paediatric concentration rangein a uniform way, the low-molecular-mass proteins Cys Cand BTP offer promising alternatives for calculating GFR,in particular in children with a decreased muscle mass orin the blind range of creatinine. In comparison with serumcreatinine, low-molecular-mass proteins have a better di-agnostic sensitivity for detection of impaired GFR [13,21].Although some caveats have to be taken into account wheninterpreting test results [22,23], the protein-based GFR716 Nephrol Dial Transplant (2009) 24: Editorial Commentscalculations only require serum values. The ongoingprogress in the standardization of these protein assays willenable the wide-scale use of these methods.Conflict of interest statement. None declared.References1. Brandt JR, Wong CS, Hanrahan JD et al. Estimating absolute glomeru-lar filtration rate in children. Pediatr Nephrol 2006; 21: 1865–18722. Schwartz GJ, Furth SL. Glomerular filtration rate measurement andestimation in chronic kidney disease.Pediatr Nephrol 2007; 22: 1839–18483. Jaffe M. Ueber den Niederschlag welchen Pikrinsa¨ure in normalenHarn erzeugt und u¨ber eine neue Reaction des Kreatinins. Z PhysiolChem 1886; 10: 391–4004. Hanser A-M, Hym B, Michotey O et al. 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Filler G, Priema F, Lepage N et al. ß-Trace Protein, cystatin C,ß2-microglobulin, and creatinine compared for detecting impairedglomerular filtration rates in children. Clin Chem 2002; 48: 729–73621. Bo¨kenkamp A, Domanetzki M, Zinck R et al. Cystatin C—a newmarker of glomerular filtration rate in children independent of ageand height. Pediatrics 1998; 101: 875–88122. Zaffanello M, Franchini M, Fanos V. Is serum cystatin-C a suitablemarker of renal function in children? Ann Clin Lab Sci 2007; 37:233–24023. Manetti L, Pardini E, Genovesi M et al. Thyroid function differentlyaffects serum cystatin C and creatinine concentrations. J EndocrinolInvest 2005; 28: 346–34924. Hari P, Bagga A, Mahajan P et al. Effect of malnutrition on serumcreatinine and cystatin C levels. Pediatr Nephrol 2007; 22: 1757–176125. Filler G, Lepage N. Should the Schwartz formula for estimation ofGFR be replaced by cystatin C formula? Pediatr Nephrol 2003; 18:981–98526. Bo¨kenkamp A, Franke I, Schlieber M et al. Beta-trace protein—amarker of kidney function in children: “Original researchcommunication-clinical investigation”. Clin Biochem 2007; 40: 969–97527. Nagao S, Fujiwara K, Imafuku N et al. Difference of carboplatinclearance estimated by the Cockroft–Gault, Jelliffe, modified-Jelliffe,Wright or Chatelut formula. Gynecol Oncol 2005; 99: 327–333Received for publication: 25.3.08Accepted in revised form: 6.5.08

How to estimate GFR in children

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