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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Improving the understanding, detection, and management of kidney disease.

Creatinine Standardization Recommendations

Background

The Creatinine Standardization Program was created by NKDEP's Laboratory Working Group in collaboration with the International Federation of Clinical Chemistry and Laboratory Medicine and the European Communities Confederation of Clinical Chemistry (now called the European Federation of Clinical Chemistry and Laboratory Medicine) to reduce interlaboratory variation in creatinine assay calibration and to enable more accurate estimates of glomerular filtration rate. The effort is part of a larger NKDEP initiative to help providers better identify and treat chronic kidney disease in order to prevent or delay kidney failure and improve patient outcomes.

Updated recommendations in this section are intended for the USA and other countries or regions that have largely completed standardization of creatinine calibration to be traceable to an isotope dilution mass spectrometry (IDMS) reference measurement procedure.

The NKDEP has developed specific creatinine measurement standardization recommendations for each of the following groups that play a critical role in the implementation of creatinine standardization worldwide. (These recommendations update those originally published in Clinical Chemistry 2006;52(1):5-18).

For countries and regions that have not yet completed standardization of creatinine calibration, see recommendations.

Contact Information

For questions about the recommendations, please contact us.

Clinical laboratories

Clinical laboratories are crucial partners in the successful implementation of the Creatinine Standardization Program. For clinical laboratories, the following steps are necessary:

1. Use a creatinine method that has calibration traceable to an IDMS reference measurement procedure. Methods based on either enzymatic or Jaffe method principles should have calibration traceable to IDMS.

2. Use the IDMS-traceable MDRD Study equation for estimating GFR for adults using creatinine results from a method that has calibration traceable to IDMS. Methods that produce results that have acceptable bias [as defined in Clinical Chemistry 2006;52(1):5-18] when compared to an IDMS-traceable method also should use the IDMS-traceable MDRD Study equation.

IDMS-traceable MDRD Study Equation

Conventional Units (creatinine as mg/dL; age in years):

GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

SI Units (creatinine as µmol/L; age in years):

GFR (mL/min/1.73 m2) = 175 × (Scr/88.4)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

(Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F. Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values. Clinical Chemistry 53:766-772,2007.)

3. Use the IDMS-traceable version of the Schwartz equation for estimating GFR for children <18 years using creatinine results from a method that has calibration traceable to isotope dilution mass spectrometry (IDMS). This equation has been referred to as the "bedside" Schwartz equation.

Bedside IDMS-traceable Schwartz Equation for Children

Conventional Units (creatinine as mg/dL; height in cm):

GFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Creatinine in mg/dL

SI Units (creatinine as µmol/L; height in cm):

GFR (mL/min/1.73 m2) = (36.2 × Height) / Serum creatinine

(Schwartz GJ, Munoz A, Schneider MF, Mak RK, Kaskel F, Warady BA, et al. New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol2009;20:629-637.)

4. Report Proficiency Testing and External Quality Assessment (PT/EQA) results for serum and urine creatinine using the correct instrument/method peer group for IDMS-traceable calibration.

5. If desired, monitor calibration performance of routine methods that have calibration traceable to an IDMS reference measurement procedure through participation in the College of American Pathologists' LN24 Survey (commutability validated), or comparable EQA with commutable samples and IDMS target values. Periodic evaluation of a creatinine method's calibration using NIST SRM 967 is another alternative that a laboratory may wish to consider.

IVD Manufacturers

In vitro diagnostic (IVD) manufacturers are crucial partners in the successful implementation of the Creatinine Standardization Program. For IVD manufacturers, the following steps are necessary:

1. Calibrate serum creatinine methods to be traceable to an isotope dilution mass spectrometry (IDMS) reference measurement procedure. Standardization of method calibration will reduce the interlaboratory bias in results and yield more accurate estimated GFR (eGFR) when using the IDMS-traceable MDRD Study equation or the IDMS traceable Schwartz equation.

2. Coordinate with customer laboratories so that, upon switching to a method with IDMS-traceable calibration, they immediately begin using the IDMS-traceable MDRD Study equation for those > 18 years old and the IDMS-traceable Schwartz equation for children.

3. Provide serum and urine creatinine reference intervals appropriate for the method.

4. Describe the relationship between creatinine results when measured by a method's original calibration and its updated version with IDMS-traceable calibration. Include detailed descriptions (including mathematical conversion factors, equations, or functions) of the impact of a calibration change for both serum and urine creatinine values, with emphasis on the 0.5 to 2.5 mg/dL (45 to 220 µmol/L) range of interest in serum. Read NKDEP's recommendations for pharmacists and authorized drug prescribers for more information on using creatinine for drug dosing.

5. Be prepared to communicate to customers important changes related to using a creatinine method with calibration traceable to IDMS.

6. Where necessary, improve the bias and precision of creatinine methods to meet the total error goal for serum creatinine measurement described in Figure 3 in the paper published in Clinical Chemistry 2006;52(1):5-18(reproduced below). This figure provides an error budget for creatinine measurement in the range 1.00-1.50 mg/dL (88.4-133 µmol/L) that will ensure less than 10 percent increase in the relative error of the eGFR. An example of method performance, in the absence of any interfering substances in the serum sample, that would achieve this total error goal is analytical imprecision (including interlaboratory calibration variability) SD < 0.08 mg/dL (7.1 µmol/L) and analytical bias (compared to an IDMS reference measurement procedure) < 0.05 mg/dL (4.4 µmol/L) at a serum creatinine concentration of 1.00 mg/dL (88.4 µmol/L). Ensure that comparable bias and imprecision extend throughout the analytical measurement range (measuring interval).

An error budget for creatinine measurement: a line graph tracks standard deviation from 1.8 to 11 micromols per liter (0.02 to 0.12 milligrams per deciliter) on the y-axis and bias from -13 to 13 micromols per liter (-0.15 to 0.15 milligrams per deciliter) on the x-axis. The line graph presents as an up-side-down U ranging from -8.8 to 8.8 micromols per liter with an apex at 0.

7. Where necessary, method bias and imprecision at concentrations <1.00 mg/dL (88.4 µmol/L) should be addressed to reduce the uncertainty in eGFR for pediatric populations, and to allow extension of reporting eGFR to values <60 mL/min/1.73 m2 with newer estimating equations.

8. Design instruments that report serum creatinine values as mg/dL to two decimal places, or as µmol/L to the nearest whole number. This will reduce the contribution of a rounding error when estimating GFR from a creatine result.

9. Address analytical nonspecificity issues in routine serum creatinine methods. The NKDEP Laboratory Working Group is currently developing recommendations for creatinine method specificity requirements.

PT/EQA Providers

Proficiency Testing and External Quality Assessment (PT/EQA) providers are crucial partners in the successful implementation of the Creatinine Standardization Program.

All major manufacturers of creatinine measurement procedures in the USA have standardized calibration of creatinine methods to be traceable to IDMS. However, there may be some smaller manufacturers who have not completed the standardization. For international programs, there may be countries that have not standardized calibration of creatinine methods. Consequently, there may be bimodal distributions among participant results depending on the calibration status of the creatinine methods used. These differences in calibration may need to be accommodated by creating appropriate instrument/method peer groups (traditional or IDMS-traceable calibration) for evaluation of results that reflect the calibration status of particular methods.

NKDEP recommends introducing a regularly recurring PT/EQA program that uses commutable serum materials with target values traceable to an IDMS reference measurement procedure for creatinine. Such a program will allow individual laboratories and IVD manufacturers, on an on going basis, to assess the performance of routine clinical laboratory methods and the success of calibration-traceability for each of their methods. However, IDMS target values should not be assigned to PT/EQA materials, nor should they be used to evaluate participant performance, unless the materials have been validated to be commutable with native clinical samples for the routine methods being evaluated.

For additional information about commutable serum reference materials and their application to PT/EQA programs, refer to: Miller WG, et al. Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Archives of Pathology and Laboratory Medicine, 2005;129(3):297-304; and Miller WG, Myers GL, Rej R. Why commutability matters. Clinical Chemistry 2006;52:553-4.

Pharmacists and Authorized Drug Prescribers

The creatinine standardization recommendations for pharmacists and authorized drug prescribers have been updated. Please visit CKD and Drug Dosing: Information for Providers.

National Metrology Institutes, Reference Laboratories, and JCTLM Member Organizations

National metrology institutes, reference laboratories, and Joint Committee for Traceability in Laboratory Medicine (JCTLM) organizational members are crucial partners in the successful implementation of the Creatinine Standardization Program. For these groups, the following steps are necessary:

1. Provide tools to assist IVD manufacturers with efforts to reduce analytical bias.

2. Develop readily available reference materials for serum creatinine with IDMS-assigned values and with validated commutability with individual patient sera for a wide variety of routine methods. The reference materials should be submitted to the JCTLM for review and acceptance. The National Institute for Standards and Technology (NIST) released SRM 967 Creatinine in Frozen Human Serum in 2007.

3. Make available a high-level reference measurement procedure with high throughput to assist in vitro diagnostic manufacturers in validating the trueness of their methods and the commutability of candidate reference materials. An ID-LC-MS/MS procedure validated to have little or no bias relative to ID-GC-MS/MS may be useful for this purpose. The reference measurement procedure and reference laboratory service should be submitted to the JCTLM for review and acceptance.

4. Additional reference laboratories are needed to meet the anticipated demand for analytical services to establish and validate traceability to the reference method.

Software Vendors

Software vendors are crucial partners in the successful implementation of the Creatinine Standardization Program. Software vendors should consider the following:

Software provided for laboratory information systems should change the equation used to estimate glomerular filtration rate to the IDMS-traceable Modification of Diet in Renal Disease (MDRD) Study equation for adults or the IDMS-traceable Schwartz equation for children. Software should provide flexibility to use older equations for laboratories that do not use IDMS-traceable equations and to use newer equations as they are developed.

Creatinine Standardization Recommendations (for countries or regions that are introducing or have not completed standardization of creatinine calibration)

Many of the recommendations for the USA and other countries or regions that have largely completed standardization of creatinine calibration to be traceable to an IDMS reference measurement procedure will be applicable and should be reviewed. Retained in this section are the older NKDEP recommendations that may be helpful for countries or regions that have not yet started or are in the process of transitioning to creatinine methods with calibration traceable to an IDMS reference measurement procedure. Recommendations are available for:

The NKDEP recommends that adoption of standardized creatinine assays and associated reference intervals and estimating equations be carried out in a consistent manner across a country or region when possible. A collaborative approach between clinicians, laboratory professionals and manufacturers will enable the best outcome.

Clinical laboratories

Recommendations for clinical laboratories that are planning to change to a creatinine method with calibration traceable to an IDMS reference measurement procedure

1. Continue using the Original Modification of Diet in Renal Disease (MDRD) Study equation for routine methods that have not been calibrated to be traceable to IDMS. It is appropriate to use this equation because most methods in this category will produce creatinine results that have a bias similar to that of the method used in developing the Original MDRD Study equation. Contact the reagent and/or calibrator manufacturer with questions about the traceability of the calibration for the method used in your laboratory.

2. Ensure immediate use of the IDMS-traceable MDRD Study equation for estimating GFR in adults, and the IDMS-traceable Schwartz equation for children, once your laboratory begins using a creatinine method that has its calibration traceable to IDMS. Methods that produce results that have acceptable bias [as defined in Clinical Chemistry 2006;52(1):5-18] when compared to an IDMS-traceable method also should use the IDMS-traceable MDRD Study or Schwartz equations.

3. Communicate the following to health care providers, including pharmacists, when using a serum creatinine method that has its calibration traceable to an IDMS reference method:

4. Report Proficiency Testing and External Quality Assessment (PT/EQA) results for serum and urine creatinine using the correct instrument/method peer group for IDMS-traceable calibration. Evaluation of EQA may be affected by bimodal distributions among participant results depending on the calibration status of the creatinine methods used. These differences in calibration may need to be accommodated by creating appropriate instrument/method peer groups (traditional or IDMS-traceable calibration) for evaluation of results that reflect the calibration status of particular methods. (See NKDEP's recommendations for PT/EQA providers.)

5. If desired, monitor calibration performance of routine methods that have calibration traceable to an IDMS reference method by participating in an EQA program that uses commutable samples and IDMS target values. Periodic evaluation of a creatinine method's calibration using NIST SRM 967 is another alternative that a laboratory may wish to consider.

IVD manufacturers

Recommendations for IVD manufacturers that are planning to introduce a creatinine method with calibration traceable to an IDMS reference measurement procedure

1. Continue using or recommending the original Modification of Diet in Renal Disease (MDRD) Study equation and the original Schwartz equation for routine methods that have not been calibrated to be traceable to IDMS.

IDMS-traceable MDRD Study Equation

Conventional Units (creatinine in mg/dL; age in years):

GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

SI Units (creatinine in µmol/L; age in years):

GFR (mL/min/1.73 m2) = 175 × (Scr/88.4)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

2. Change the calibration of creatinine methods to be traceable to an isotope dilution mass spectrometry (IDMS) reference measurement procedure. Standardization of method calibration will reduce the interlaboratory bias in results and yield more accurate estimated GFR (eGFR) when using the IDMS-traceable MDRD Study Equation or the IDMS traceable Schwartz equation.

3. Coordinate with customer laboratories so that, upon switching to a method with IDMS-traceable calibration, they immediately begin using the IDMS-traceable versions of both the MDRD Study equation for those >18 years old and the Schwartz equation for children.

4. Provide serum and urine creatinine reference intervals appropriate for the method.

5. Describe the relationship between creatinine results when measured by a method's original calilbration and its updated version with IDMS-traceable calibration. Include detailed descriptions (including mathematical conversion factors, equations, or functions) of the impact of a calibration change for both serum and urine creatinine values, with emphasis on the 0.5 to 2.5 mg/dL (45 to 220 µmol/L) range of interest in serum. Read NKDEP's recommendations for pharmacists and authorized drug prescribers) for more information on using creatinine for drug dosing.

6. Be prepared to communicate to customers important changes related to using a creatinine method with calibration traceable to IDMS.

7. Emphasize that creatinine measurements at the lower concentrations usually observed in pediatric patients have greater measurement variability than for values seen in adults. Estimates of kidney function based on these values also will have greater variability than for adults.

8. Where necessary, improve the bias and precision of creatinine methods to meet the total error goal for serum creatinine measurement described in Figure 3 in the paper published in Clinical Chemistry 2006;52(1):5-18 (reproduced below). This figure provides an error budget for creatinine measurement in the range 1.00-1.50 mg/dL (88.4-133 µmol/L) that will ensure less than 10 percent increase in the relative error of the eGFR. An example of method performance, in the absence of any interfering substances in the serum sample, that would achieve this total error goal is analytical imprecision (including interlaboratory calibration variability) SD < 0.08 mg/dL (7.1 µmol/L) and analytical bias (compared to an IDMS reference measurement procedure) < 0.05 mg/dL (4.4 µmol/L) at a serum creatinine concentration of 1.00 mg/dL (88.4 µmol/L). Ensure that comparable bias and imprecision extend throughout the analytical measurement range (measuring interval).

An error budget for creatinine measurement: a line graph tracks standard deviation from 1.8 to 11 micromols per liter (0.02 to 0.12 milligrams per deciliter) on the y-axis and bias from -13 to 13 micromols per liter (-0.15 to 0.15 milligrams per deciliter) on the x-axis. The line graph presents as an up-side-down U ranging from -8.8 to 8.8 micromols per liter with an apex at 0.

9. Where necessary, method bias and imprecision at concentrations < 1.00 mg/dL (88.4 µmol/L) should be addressed to reduce the uncertainty in eGFR for pediatric populations, and to allow extension of reporting eGFR to values <60 mL/min/1.73 mM2 with newer estimating equations.

10. Design instruments that report serum creatinine values as mg/dL to two decimal places, or as µmol/L to the nearest whole number. This will reduce the contribution of a rounding error when estimating GFR from a creatinine result.

11. Address analytical nonspecificity issues in routine serum creatinine methods. The NKDEP Laboratory Working Group is currently developing recommendations for creatinine method specificity requirements.

12. Communicate with Proficiency Testing and External Quality Assessment Scheme (PT/EQA) providers to inform them when a revised creatinine calibration will become effective, and work with PT/EQA providers to develop appropriate instrument/method peer groups for participants to be evaluated appropriately.

PT/EQA providers

Recommendations for PT/EQA providers during the transition to creatinine methods with calibration traceable to an IDMS reference measurement procedure

1. Advise participant laboratories that you will collaborate with in vitro diagnostic (IVD) manufacturers to ensure appropriate grading of PT/EQA data during a transition period for implementation.

2. Make necessary changes in participant grading within your respective survey programs during the transition of routine creatinine methods to revised calibrations that are traceable to an isotope dilution mass spectrometry (IDMS) reference method. It is anticipated that bimodal distributions of survey results within a method may be observed during the transition period. When this occurs, it will most likely be the result of groups of laboratories independently transitioning to new creatinine calibrations for a particular method. This should not be a cause for a given laboratory to fail a PT/EQA challenge. Thus, it may be necessary for PT/EQA providers to collaborate with IVD manufacturers to create new instrument/method peer groups (traditional or IDMS-traceable calibration) for their participants that reflect the calibration status of each method that is undergoing a calibration transition for both serum and urine creatinine values.

3. Inform participant laboratories that they will need to choose the correct instrument/method peer group (sub-classified as traditional or IDMS-traceable calibration) for the creatinine calibration in use by their laboratory for a given PT/EQA challenge.

4. Request IVD manufacturers' expected dates for introduction of IDMS-traceable calibrations for creatinine for each of their methods, and the anticipated timeframe to achieve completion of the transition for a given method to the new calibration in all routine clinical laboratories using that method around the world.

NKDEP recommends introducing a regularly recurring PT/EQA program that uses commutable serum materials with target values traceable to an IDMS reference measurement procedure for creatinine. Such a program will allow individual laboratories and IVD manufacturers, on an ongoing basis, to assess the performance of routine clinical laboratory methods and the success of calibration-traceability for each of their methods. However, IDMS target values should not be assigned to PT/EQA materials, nor should they be used to evaluate participant performance, unless the materials have been validated to be commutable with native clinical samples for the routine methods being evaluated.

For additional information about commutable serum reference materials and their application to PT/EQA programs, refer to: Miller WG, et al. Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Archives of Pathology and Laboratory Medicine, 2005;129(3):297-304; and Miller WG, Myers GL, Rej R. Why commutability matters. Clinical Chemistry 2006;52:553-4.

Pharmacists and authorized drug prescribers

Recommendations for Pharmacists and Authorized Drug Prescribers when using results from creatinine methods with calibration traceable to an IDMS reference measurement procedure

The creatinine standardization recommendations for pharmacists and authorized drug prescribers have been updated. Please visit CKD and Drug Dosing: Information for Providers.

Page last updated: March 1, 2012