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Reevaluation of formulas for predicting creatinine clearance in adults and children, using compensated creatinine methods.

In clinical practice, glomerular filtration rate (GFR) is the most important marker for evaluation of renal function (1). Dosages of drugs that are eliminated by glomerular filtration are often based on GFR. At present, the most reliable methods for accurate assessment of overall GFR require intravenous administration of exogenous compounds and are both cumbersome and expensive. In clinical practice, creatinine clearance (CrCI) is widely accepted as a simple measure of GFR. However, CrCl systematically overestimates GFR because creatinine is freely filtered by the glomerulus and is also secreted by the proximal tubule. In the earliest methods, serum creatinine was assayed by the Jaffe reaction after deproteinization, eliminating the pseudo-chromogen effect of proteins (2). Similarly, the first automated methods used dialysis membranes to prevent interference from plasma proteins. Today, however, analyzers use undiluted serum and plasma, making them subject to the so-called "protein error" (3). This produces a positive difference of -27 [micro]mol/L creatinine compared with HPLC methods (4-7). Because urine contains relatively little or no protein, the protein error affects only creatinine determinations in serum. Therefore, CrCl is underestimated when creatinine methods affected by protein error are used. This underestimation has been stated to be compensated by the overestimation attributable to tubular secretion of creatinine. However, studies confirming this statement are lacking.

In compensated Jaffe methods, the values assigned to the calibrator set point are adjusted to minimize the pseudo-creatinine contribution of proteins. The result is that compensated methods produce lower creatinine values. Alternatively, the protein error can be avoided by use of enzymatic creatinine methods. Collection of timed urine for CrCl is often a major source of error; therefore, simple formulas have been introduced to estimate GFR based on serum creatinine concentration, age, gender, body weight, and body length (8-13); these formulas thus do not require urine collections. However, it is not always clear which creatinine method was used when applying these formulas.

We examined 80 patients [33 males (age range, 51-74 years) and 47 females (age range, 56-81 years)] referred for nuclear medicine clearance ("Cr-EDTA clearance) before chemotherapy because of renal insufficiency or for nephrologic evaluation (geriatric patients). We also examined 27 pediatric patients [15 males (7-17 years) and 12 females (6-17 years)], in whom inulin clearance had been determined for nephrologic evaluation of a nephroblastoma or because they had received nephrotoxic drugs. Clearance determinations succeeded in 23 children. In 4 children, urine collections were inadequate.

The elimination rate of "Cr-EDTA was measured according to the methods of Chantler and coworkers (14,15) and Van de Wiele et al. (16). Inulin clearance was determined by an enzymatic assay (17). Serum creatinine was measured by a standard HPLC method (18). Serum and urinary creatinine were measured on a Modular P analyzer with commercial reagents (Roche): (a) a kinetic rate-blanked Jaffe assay based on the modified kinetic alkaline picrate method (19); (b) a kinetic rate-blanked Jaffe compensated assay for reactive proteins according to the manufacturer's instructions; (c) an enzymatic assay using the Creatinine Plus method (20-22). Serum total protein, albumin, urea nitrogen, uric acid, and total bilirubin were measured with use of commercial reagents (Roche).

CrCls were calculated according to the formula: UV/Pt, where U represents the urinary creatinine concentration ([micrp]mol/L), V is urinary collection volume (mL), P is serum creatinine concentration ([micro]mol/L), and t is urinary collection time (1440 min). In children, CrCl values were corrected for body surface. CrCl values were also calculated according to the Cockcroft-Gault method (8) and the abbreviated Modification of Diet in Renal Disease Study (MDRD) method (9, 10) in adults and the method of Schwartz and coworkers (11-13) in children.

Values are expressed as the median (interquartile range). Methods were compared using the Pearson correlation coefficient. Correlation studies were performed according to Bland and Altman (23).

Median serum creatinine concentrations in adults were 183.2 (84.8-204.5) [micro]mol/L by HPLC, 173.8 (72.3-207.7) [micro]mol/L by the enzymatic assay, 178.2 (89.1-213.7) [micro]mol/L by the uncompensated Jaffe method, and 174.7 (71.6-207.3) [micro]mol/L by the compensated Jaffe method. Linear regression equations for serum creatinine in adults were as follows:

Enzymatic method (y) vs HPLC (x): y ([micro]mol/L) = 0.96x ([micro]mol/L) - 2.47 [micro]mol/L (r = 0.98)

Compensated Jaffe (y) vs uncompensated Jaffe method (x): y ([micro]mol/L) = 0.95x ([micro]mol/L) + 0.44 [micro]mol/L (r = 0.98)

Uncompensated Jaffe method (y) vs HPLC (x): y ([micro]mol/ L) = 0.84x ([micro]mol/L) + 24.94 [micro]mol/L (r = 0.98).

The equations demonstrate an overestimation of serum creatinine by the uncompensated Jaffe method in the range <155 [micro]mol/L and an underestimation in the higher range compared with the HPLC serum creatinine results. (Additional tables and figures are available as a Data Supplement accompanying the online version of this Technical Brief at vo149/issue6 /).

Effects of patient variables (gender, age, and body mass index) and concentrations of uric acid, bilirubin, total protein, albumin, and creatinine on the differences between creatinine methods were studied in detail. In a multivariate regression model, we found a highly significant correlation (P <0.0001) only between the serum uncompensated Jaffe creatinine concentration and the difference between uncompensated Jaffe and enzymatic serum creatinine concentrations (Fig. 1A). This difference between the uncompensated Jaffe and enzymatic creatinine methods was age dependent when children and adults were examined together (Fig. 1B). In the overall group of adults, we observed no impact of patient variables, including age, or of the concentrations of other substances on the difference between the creatinine methods. However, in a subgroup of nephrotic patients (n = 9) presenting with extremely low serum protein concentrations (<50 g/L), we observed a smaller positive difference attributable to pseudo-chromogens (median, 15 [micro]mol/L; interquartile range, 12-19 [micro]mol/L; P <0.05).

The median (interquartile range) CrCl values in adults (n = 80) were 43.4 (15.3-74.2) [micro]mol/L for the HPLC, 49.6 (15.3-76.7) [micro]mol/L for the enzymatic, 37.5 (14.9-56.8) [micro]mol/L for the uncompensated Jaffe, and 48.0 (15.8-74.6) [micro]mol/L for the compensated Jaffe creatinine methods. The linear regression statistics are shown in Table 1.


Cockcroft-Gault estimates of clearance in adults (n = 80) produced median (interquartile range) values of 48.3 (24.5-69.5) [micro]mol/L for the HPLC, 55.0 (24.4-78.7) [micro]mol/L for the enzymatic, 46.0 (23.2-64.5) [micro]mol/L for the uncompensated Jaffe, and 53.2 (24.5-75.5) [micro]mol/L for the compensated Jaffe methods. The linear regression statistics are shown in Table 1. Abbreviated MDRD estimated clearance in adults (n = 80) produced median (interquartile range) values of 50.3 (25.9-74.8) [micro]mol/L for the HPLC, 58.7 (26.1-92.4) [micro]mol/L for the enzymatic, 47.1 (26.0-71.8) [micro]mol/L for the uncompensated Jaffe, and 56.3 (25.7-88.7) [micro]mol/L for the compensated Jaffe methods. The linear regression statistics are shown in Table 1.

Schwartz estimated clearance in children (n = 23) produced median (interquartile range) values of 173.8 (127.8-193.7) [micro]mol/L for the enzymatic, 108.4 (87.1114.8) [micro]mol/L for the uncompensated Jaffe, and 169.5 (116.3-179.9) [micro]mol/L for the compensated Jaffe methods. For the inulin clearance, the median (interquartile range) was 123.1 (97.3-152.8) mL/min (n = 23). Linear regression equations are shown in Table 1 (n = 23).

Median GFRs estimated by the Cockcroft-Gault equation varied by as much as 18%, depending on the creatinine method used. Similarly, median GFRs estimated by the MDRD equation varied as much as 20%. In adults, the use of the enzymatic method produced the highest estimated GFR and the uncompensated Jaffe the lowest regardless of the equation used.

We observed marked differences among the various methods for serum creatinine. Because they were affected by the protein error, uncompensated Jaffe methods produced higher serum creatinine results, whereas the results obtained with the compensated Jaffe, enzymatic, and HPLC creatinine methods were comparable. The difference between the uncompensated Jaffe and the enzymatic method depended mainly on the underlying concentration of serum creatinine. We observed no impact of patient variables or other substances. Because of their lower serum creatinine concentrations, we observed a relatively higher difference between the uncompensated Jaffe and enzymatic serum creatinine methods in children. In infants, who generally present with a higher protein error and even lower serum creatinine concentrations, a larger difference between these two creatinine methods is to be expected.

In adults, the uncompensated Jaffe CrCl was lower than the "Cr-EDTA clearance. In contrast, enzymatic and compensated Jaffe CrCl values were slightly higher, which is attributable to a relatively small tubular secretion of creatinine (24, 25). The Cockcroft-Gault and abbreviated MDRD algorithms for calculating GFR correlated closely with [sup.15]Cr-EDTA clearance when calculated with the creatinine results from the HPLC, enzymatic, and rate-blanked compensated Jaffe methods. However, the results obtained with the same algorithms were lower than the 51Cr-EDTA clearance when based on uncompensated Jaffe test results. The abbreviated MDRD and Cockcroft-Gault equations correlated well.

The median GFRs obtained with the Schwartz equation varied by 39%, depending on the creatinine method used. In children, the use of the enzymatic method produced the highest estimated GFR and the uncompensated Jaffe the lowest.

In children, practical problems in timed urine collection have contributed largely to the widespread use of calculated CrCl values based on serum or plasma creatinine concentration and body length. In contrast to the results for adults, the results obtained with Schwartz CrCl values in children and infants are significantly higher (in our series up to twofold higher in 4 of 23 cases) than inulin clearances when the compensated Jaffe or enzymatic creatinine method is used. If the noncompensated Jaffe test is used, the negative analytical effect of the protein error on CrCl is countered by the positive physiologic effect of the relatively more important tubular secretion of creatinine. Because serum creatinine values are lower in children, especially between ages 1 and 3 years, relative differences between compensated and noncompensated creatinine methods are very important.

Care should be taken when using estimated GFRs based on CrCl algorithms for drug administration, in particular for drugs such as cis-platinum and aminoglycoside antibiotics. In the example of the cytostatic drug cis-platinum, it is recommended to administer one-half the dose when CrCl decreases to <60 mL/min.

In conclusion, because collection of timed urine is cumbersome and susceptible to errors, calculated GFRs (Cockcroft-Gault and MDRD algorithms in adults and Schwartz algorithm in children) are often used. However, care should be taken in the choice of the serum creatinine method when applying these formulas.

We wish to thank Dr. G. Klein, Prof. W. Hoelzel, and Dr. Engel (Roche) for kindly providing the diagnostic reagent sets for this study.


(1.) Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48:699-702.

(2.) Jaffe M. Lieber den Niederschlag welchen Pikrinsaure in normalen Ham erzeugt and uber eine neue Reaction des Kreatinins. Z Physiol Chem 1886;10:391-400.

(3.) Hanser A-M, Hym B, Michotey 0, Gascht D, Marchal A, Minery M, et al. Comparaison des methodes de dosage de la creatinine serique. Ann Biol Clin 2001;59:737-42.

(4.) Zawta B, Delanghe J, Van Den Noortgate N, Taes Y, Lameire N, Engel W. Arithmetic compensation for pseudo-creatinine Jaffe method and its effect on creatinine clearance results. Clin Chem 2001;47:A148-9.

(5.) Mandell EE, Jones FL. Studies in nonprotein nitrogen. III. Evaluation of methods measuring creatinine. J Lab Clin Med 1953;41:323-34. 1 Dryers

(6.) Doolan PD, Alpen EL, Theil GB. A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Am J Med 1962;32:65-79.

(7.) Young DS, Pestaner LC, Gibberman V. Effects of drugs on clinical laboratory tests. Clin Chem 1975;21:1D-432D.

(8.) Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

(9.) National Kidney Foundation Inc: K/DOQI. Clinical practice guidelines for chronic kidney disease. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Guideline 4. Estimation of GFR. Am J Kidney Dis 2002;39:S76-110.

(10.) Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.

(11.) Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259-63.

(12.) Schwartz GF, Gauthier B. A simple estimate of glomerular filtration in adolescent boys. J Pediatr 1985;106:522-6.

(13.) Schwartz GF, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr 1984;104:84954.

(14.) Chantler C, Garnett ES, Parsons V, Veall N. Glomerular filtration rate measurement in man by the single injection method using 51Cr-EDTA. Clin Sci 1969;37:169-80.

(15.) Chantler C, Barratt TM. Estimation of glomerular rate from plasma clearance of 51-chromium edetic acid. Arch Dis Child 1972;47:613-7.

(16.) Van de Wiele C, Van Den Eeckhaut A, Venaeire W, Van Haelst JP, Versijpt J, Dierickx RA. Absolute 24 h quantification of "'Tc-DMSA uptake in patients with severely reduced kidney function: a comparison with "Cr-EDTA clearance. Nucl Med Commun 1999;20:829-32.

(17.) Delanghe J, Bellon J, De Buyzere M, Van Daele G, Leroux-Roeis G. Elimination of glucose interference in enzymatic determination of inulin. Clin Chem 1991;37:2017-8.

(18.) Zwang L, Blijenberg BG. Assessment of a selected method for creatinine with special emphasis on bilirubin interference. Eur J Clin Chem Clin Biochem 1991;29:795-800.

(19.) Bartels H, Bohmer M, Heierli C. Serum creatinine determination without protein precipitation. Clin Chim Acta 1972;37:193-7.

(20.) Goren MP, Osborne S, Wright RK. A peroxidase-coupled kinetic enzymatic procedure evaluated for measuring serum and urinary creatinine. Clin Chem 1986;32:548-51.

(21.) Guder WG, Hoffmann GE. Multicentre evaluation of an enzymatic method for creatinine determination using a sensitive colour reagent. J Clin Chem Clin Biochem 1986;24:889-902.

(22.) Lindback B, Bergman A. A new commercial method for the enzymatic determination of creatinine in serum and urine evaluated: comparison with a kinetic Jaffe method and isotope dilution-mass spectrometry. Clin Chem 1989;35:835-7.

(23.) Bland JM, Altman DG. Statistical method for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-10.

(24.) Rehberg PB. Studies on kidney function. I. The rate of filtration and reabsorption in the human kidney. Biochem J 1926;20:447-60.

(25.) Shemesh 0, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985;28:830-8.

Birgitte Wuyts, [1] Dirk Bernard, [2] Nele Van Den Noortgate, [3] Johan Van De Walle, [4] Bruno Van Vlem, [3] Rita De Smet, [3] Frank De Geeter, [5] Raymond Vanholder, [3] and Joris R. Delanghe [1] *

([1] Department of Clinical Chemistry, [3] Nephrology Section, Department of Internal Medicine, and [4] Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, B9000 Gent, Belgium; Departments of [2] Clinical Chemistry and [5] Nuclear Medicine, AZ St Jan, Ruddershove 10, B8000 Brugge, Belgium; * author for correspondence: fax 32-9240-4985, e-mail joris.delanghe@
Table 1. Linear regression statistics for the various
creatinine methods.

y (a) x Slope
Creatinine 9b0
 HPLC [sup.51]Cr-EDTA 0.88
 Enzymatic [sup.51]Cr-EDTA 1.06
 Compensated Jaffe [sup.51]Cr-EDTA 1.00
 Uncompensated Jaffe [sup.51]Cr-EDTA 0.69
Cockcroft-Gault algorithm (b)
 HPLC [sup.51]Cr-EDTA 0.96
 Enzymatic [sup.51]Cr-EDTA 1.06
 Compensated Jaffe [sup.51]Cr-EDTA 0.99
 Uncompensated Jaffe [sup.51]Cr-EDTA 0.74
Abbreviated MDRD (b)
 HPLC [sup.51]Cr-EDTA 0.92
 Enzymatic [sup.51]Cr-EDTA 1.21
 Compensated Jaffe [sup.51]Cr-EDTA 1.12
 Uncompensated Jaffe [sup.51]Cr-EDTA 0.80
Schwartz algorithm (c)
 Enzymatic Inulin 1.14
 Compensated Jaffe Inulin 1.11
 Uncompensated Jaffe Inulin 0.46

y (a) mL/min r
Creatinine 9b0
 HPLC 9.77 0.87
 Enzymatic -1.99 0.87
 Compensated Jaffe -0.88 0.88
 Uncompensated Jaffe 3.96 0.82
Cockcroft-Gault algorithm (b)
 HPLC 1.93 0.90
 Enzymatic 2.77 0.90
 Compensated Jaffe 4.61 0.90
 Uncompensated Jaffe 9.75 0.87
Abbreviated MDRD (b)
 HPLC 5.32 0.81
 Enzymatic -0.45 0.86
 Compensated Jaffe 1.67 0.86
 Uncompensated Jaffe 7.99 0.85
Schwartz algorithm (c)
 Enzymatic 18.89 0.76
 Compensated Jaffe 18.73 0.65
 Uncompensated Jaffe 46.62 0.64

(a) y = clearance (mL/min) based on the method specified.

(b) In adults (n = 80).

(c) In children (n = 23).
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Title Annotation:Technical Briefs
Author:Wuyts, Birgitte; Bernard, Dirk; Van Den Noortgate, Nele; Van De Walle, Johan; Van Vlem, Bruno; De Sm
Publication:Clinical Chemistry
Date:Jun 1, 2003
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