In 2006, the Laboratory Working Group of the National Kidney Disease Education Program (NKDEP) published recommendations to standardize serum creatinine measurements to improve the accuracy of the values reported by clinical laboratories (1). By the end of 2009, most laboratories were using methods that had been recalibrated, and the College of American Pathologists no longer separated the creatinine survey results by the calibration traceability of the method. While the global effort to standardize creatinine assays to isotope-dilution mass spectrometry (IDMS) is now old news, many pertinent clinical questions still remain to be answered.
The change in creatinine values as a result of the method recalibration has been well reported. IDMS-traceable creatinine values are 10-20% lower than values generated by non-IDMS calibrated methods. This decreased creatinine value leads to a falsely elevated glomerular filtration rate (GFR) and creatinine clearance (CrCl) when the value is plugged into traditional estimating equations or used in calculations. The most common equations used to estimate glomerular filtration rate in adults and children, the MDRD equation and the Schwartz equation, respectively, have been re-expressed and can be used with IDMS-traceable creatinine values to give accurate estimations of GFR. The Cockcroft-Gault (CG) equation, which is used to estimate creatinine clearance and is the equation used by the pharmaceutical industry for drug dosage adjustment recommendations, cannot be re-expressed to be used with IDMS-traceable creatinine values.
What are the recommendations for dosing of nephrotoxic drugs or drugs with narrow therapeutic windows since the CG equation gives falsely elevated estimations of creatinine clearance with IDMS-traceable creatinine values? The NKDEP suggested several approaches on its website in 2010 (2). Since non-standardized creatinine methods had substantial variability, the original pharmacokinetic studies that were done to set the dosing guidelines also contained this variability. This was further exacerbated by the variability of creatinine measurements in various laboratories where patient testing was done in order to determine the correct drug dose for each patient. It is not feasible for the drug manufacturers to re-express drug dosing recommendations for IDMS-traceable creatinine values, but even when using the CG equation, there will now be more consistent drug dosing due to less variation in estimations of kidney function.
Another suggestion was to use eGFR for drug dosing as well as patient management. A large study by Stevens and collaborators compared the MDRD equation and two versions of the CG equation to measured GFR (3). The MDRD equation had greater concordance with measured GFR in placing patients in the correct FDA-assigned kidney function categories at 78%, compared to the two CG equations, which had concordance rates of 73% and 66%, respectively. When dosing recommendations generated by the different equations were compared, there was a concordance rate of 89% and 88% between the MDRD and each CG equation. Use of the MDRD equation could be used for drug dosing in the majority of patients, but for those whose eGFR and eCrCl are quite different or for whom estimation based on creatinine might be inaccurate, it is recommended to measure either CrCl or GFR directly.
One patient population that has not been studied in regard to this question is children. eGFR in children is calculated by the Schwartz equation, not the MDRD equation, and there have been no studies comparing use of the Schwartz equation to CG for drug dosing purposes. This is an important issue because children generally have lower values of creatinine when compared to adults, and the 10-20% difference in creatinine at the lower end of the range contributes to a larger inaccuracy in eCrCl.
How have the clinicians in your institution reacted to the change in creatinine calibration? Did your phone ring off the hook with questions or was it not even noticed? What kind of interactions did you have with your pharmacy before and after the change took affect?
- Myers GL, Miller WG, Coresh J et al. Recommendations for improving serum creatinine measurements: A report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem 2006;52:5-18.
- National Kidney Disease Education Program. http://nkdep.nih.gov (Accessed April 2011).
- Stevens LA, Nolin TD, Richardson MM, Feldman HI, Lewis JB, Rodby R, et al. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis 2009;54:33-42.