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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

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

CKD and Drug Dosing: Information for Providers

Estimation of Kidney Function for Prescription Medication Dosage in Adults

Knowledge of kidney function is important for dosage of medications that are excreted by the kidneys. Food and Drug Administration (FDA)-approved drug-labeling guides provide adjustments of drug dosages for patients with impaired kidney function. On these labels, serum creatinine; measured creatinine clearance (CrCl); or, most commonly, estimated creatinine clearance using the Cockcroft-Gault equation (eCrCl) are used to estimate kidney function. For most drugs, these labels were developed prior to standardized calibration of creatinine assays and reporting estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) Study equation1 or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.13 This document describes the National Kidney Disease Education Program's (NKDEP) suggestions and rationales for assessment of kidney function for drug-dosing purposes.

NKDEP's Suggested Approach to Drug Dosing

Historically, there has been substantial variability in serum creatinine values reported by different clinical laboratory creatinine methods. Consequently, pharmacokinetic (PK) studies performed using nonstandardized creatinine methods obtained results that were dependent upon the particular creatinine method used in a given PK study. The results from the PK studies were incorporated into FDA drug labels. As such, the PK studies' recommended drug dosages (i.e., the FDA drug labels) were inconsistently translated into clinical practice due to the variability among creatinine methods used in different laboratories.

Use of standardized creatinine methods will lead to less variation in estimating kidney function and more consistent drug dosing. For some drugs, the FDA or manufacturers may decide to perform studies to re-express drug labeling for standardized creatinine values. However, it will not be possible to re-express all current drug-dosing recommendations for use with standardized creatinine values.

A large simulation study compared eGFR and eCrCl calculated from standardized creatinine values to each other and to gold-standard measurements of GFR. The results suggested that for the majority of patients and for most drugs tested, there was little difference in the drug dose that would be administered using either equation to estimate kidney function.2 Based on these and other considerations, we suggest the following:

Impact of IDMS-standardized Creatinine Values

National efforts to standardize serum creatinine assays by establishing calibration traceability to an isotope dilution mass spectrometry (IDMS) reference measurement procedure began in 2005. All major global manufacturers have completed recalibration to be traceable to an IDMS reference measurement procedure, and inventory with older calibration should no longer be in use. (Individual manufacturers should be contacted for status regarding their products.) Previously, there was a large variability in serum creatinine results among clinical laboratories, with an overall positive bias by approximately 10 to 20 percent among laboratories surveyed.5 Now that standardization of the majority of creatinine methods to IDMS-traceable calibration is complete, there will be less variability in creatinine results used for managing patients. The following items describe the impact of standardized creatinine assays:

MDRD Study Equation

CKD-EPI Equation

Cockcroft-Gault Equation

Limitations of Any Serum Creatinine-based Estimate

1 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;145:247-54.

2 Stevens LA, Nolin T, Richardson M, et al. Comparison of Drug Dosing Recommendations Based on Measured GFR and Kidney Function Estimating Equations. Am J Kid Dis. 2009;54(1):33-42.

3 Mosteller, RD. Simplified Calculation of Body-Surface Area. N Engl J Med. 1987;317(17):1098.

4 Stevens LA, Levey AS. Measured GFR as a Confirmatory Test for Estimated GFR: Indications and Interpretation. J Am Soc Nephrol. 2009;20:2305-13.

5 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.

6 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.M/

7 Levey AS, Bosch JP, Lewis JB, et al. 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.

8 Stevens LA, Coresh J, Greene T, et al. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med. 2006;354:2473-83.

9 Stevens LA, Coresh J, Feldman HI, et al. Evaluation of the modification of diet in renal disease study equation in a large diverse population. J Am Soc Nephrol. 2007;18:2749-57.

10 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;53:766-72.

11 Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

12 Poggio ED, Nef PC, Wang X, et al. Performance of the Cockcroft-Gault and modification of diet in renal disease equations in estimating GFR in ill hospitalized patients. Am J Kidney Dis. 2005;46:242-52.

13 Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.

Page last updated: April 28, 2015