Objectives: Estimating equations using serum creatinine (SCr) are often used to assess glomerular filtration rate (GFR). Such creatinine (Cr)-based formulae may produce biased estimates of GFR when using Cr measurements that have not been calibrated to reference laboratories. In this paper, we sought to examine the degree of this variation in Cr assays in several laboratories associated with academic medical centers affiliated with the Chronic Renal Insufficiency Cohort (CRIC) Study; to consider how best to correct for this variation, and to quantify the impact of such corrections on eligibility for participation in CRIC. Variability of Cr is of particular concern in the conduct of CRIC, a large multicenter study of subjects with chronic renal disease, because eligibility for the study depends on Cr-based assessment of GFR. Methods: A library of 5 large volume plasma specimens from apheresis patients was assembled, representing levels of plasma Cr from 0.8 to 2.4 mg/dl. Samples from this library were used for measurement of Cr at each of the 14 CRIC laboratories repetitively over time. We used graphical displays and linear regression methods to examine the variability in Cr, and used linear regression to develop calibration equations. We also examined the impact of the various calibration equations on the proportion of subjects screened as potential participants who were actually eligible for the study. Results: There was substantial variability in Cr assays across laboratories and over time. We developed calibration equations for each laboratory; these equations varied substantially among laboratories and somewhat over time in some laboratories. The laboratory site contributed the most to variability (51% of the variance unexplained by the specimen) and variation with time accounted for another 15%. In some laboratories, calibration equations resulted in differences in eligibility for CRIC of as much as 20%. Conclusions: The substantial variability in SCr assays across laboratories necessitates calibration of SCr measures to a common standard. Failing to do so may substantially affect study eligibility and clinical interpretations when they are determined by Cr-based estimates of GFR.

Keywords:
Chronic renal disease, Creatinine measurements, variability, Chronic Renal Insufficiency Cohort (CRIC) Study, Glomerular filtration rate
1.
Coresh J, Selvin E, Stevens LA, et al: Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038–2047.
2.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296–1305.
3.
Hsu CY, Chertow GM, Curhan GC: Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 2002;61:1567–1576.
4.
Ross JW, Miller WG, Myers GL, Praestgaard J: The accuracy of laboratory measurements in clinical chemistry: a study of 11 routine chemistry analytes in the College of American Pathologists Chemistry Survey with fresh-frozen serum, definitive methods, and reference methods. Arch Pathol Lab Med 1998;122:587–608.
5.
Coresh J, Toto RD, Kirk KA, et al: Creatinine clearance as a measure of GFR in screenees for the African-American Study of Kidney Disease and Hypertension pilot study. Am J Kidney Dis 1998;32:32–42.
6.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1–12.
7.
Clase CM, Garg AX, Kiberd BA: Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey NHANES III). J Am Soc Nephrol 2002;13:1338–1349.
8.
Coresh J, Eknoyan G, Levey AS: Estimating the prevalence of low glomerular filtration rate requires attention to the creatinine assay calibration. J Am Soc Nephrol 2002;13:2811–2812.
9.
Feldman HI, Appel LJ, Chertow GM, et al: The Chronic Renal Insufficiency Cohort (CRIC) Study: design and methods. J Am Soc Nephrol 2003;14:S148–S153.
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;130:461–470.
11.
Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function–measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–2483.
12.
Miller WG, Myers GL, Ashwood ER, et al: Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Arch Pathol Lab Med 2005;129:297–304.
13.
Verhave JC, Fesler P, Ribstein J, du Cailar G, Mimran A: Estimation of renal function in subjects with normal serum creatinine levels: influence of age and body mass index. Am J Kidney Dis 2005;46:233–241.
14.
Coresh J, Astor BC, McQuillan G, et al: Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39:920–929.
15.
Stevens LA, Manzi J, Levey AS, et al: Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. Am J Kidney Dis 2007;50:21–35.
16.
Murthy K, Stevens LA, Stark PC, Levey AS: Variation in the serum creatinine assay calibration: a practical application to glomerular filtration rate estimation. Kidney Int 2005;68:1884–1887.
17.
Myers GL, Miller WG, Coresh J, et al: Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem 2006;52:5–18.
18.
Levey AS, Coresh J, Greene T, et al: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–254.
19.
Levey AS, Coresh J, Greene T, et al: Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem 2007;53:766–772.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.