Assessment of kidney function for drug dosing.

The effort to improve the identification and management of patients with chronic kidney disease (CKD) is based on implementing more precise means of assessing kidney function and kidney damage in the clinical setting. Over the past decade, the clinical chemistry community has adopted routine reporting of estimated GFR (eGFR) calculated from the Modification of Diet in Renal Disease (MDRD) Study equation and is implementing a creatinine standardization program to enable the manufacturers of laboratory methods to establish calibration traceability to an isotope-dilution mass spectrometry (IDMS) reference measurement procedure. As a result, routine reporting of eGFR for adults based on an IDMS-traceable creatinine is becoming the clinical standard for patient care (1, 2 ). As with all changes in clinical practice, the implementation of eGFR reporting and creatinine standardization has created some uncertainty and confusion among health care providers. A focus of concern is the assessment of kidney function for drug dosing adjustment. Standardizing creatinine calibration to an IDMS reference produces a lowering of creatinine values by 10%–20% for most methods. Pharmaceutical manufacturers have used the Cockcroft–Gault (CG) equation to estimate creatinine clearance as the basis for drug dose adjustment recommendations, and there is no modified equation available for use with the IDMStraceable creatinine results. Consequently, creatinine clearance estimated from the CG equation will be erroneously high. Because eGFR using the MDRD Study equation is relatively new, eGFR data is not part of drug safety information or package inserts approved by the US Food and Drug Administration (FDA). Clinicians are most concerned about dosing highly toxic drugs with narrow therapeutic indices, particularly carboplatin, an antineoplastic agent. Some clinical chemists have experienced resistance to creatinine standardization from clinicians in their facilities based on their uncertainty about how standardization would affect their ability to dose drugs such as carboplatin. Other clinicians have responded by requesting back-calculation to a nonstandardized creatinine which can then be used in the CG equation. Both of these responses reflect some misunderstanding about creatinine measurement. The first misunderstanding concerns the nature of estimating equations. The goal is to develop an equation that produces an eGFR which is closest to a gold standard, in this case a measured GFR. Estimating equations are developed from populations of patients and will give results that reflect the mean GFR of the population in which they were developed. However, the actual GFR of any individual will be distributed about that mean value. Thus, an estimating equation provides the “best guess” of the GFR of a patient based on patient-specific values supplied for the variables used in that equation (in the case of the MDRD Study equation, age, sex, race, and creatinine); however, it needs to be emphasized that such an estimated GFR is not the patient’s actual GFR. It has been demonstrated that the MDRD Study equation is superior to the CG equation in predicting kidney function in most people (3 ). The second misunderstanding concerns the impact of nonstandardized creatinines on the CG equation. Although the CG estimation has been the traditional means of assessing kidney function and is the method with which pharmacists and clinicians have become comfortable, it has been subject to the variation in creatinine values that occurred before standardization. Rather than providing a clinical gold standard, Cockcroft–Gault equation estimates varied depending on the creatinine method used in any given facility. Because this variation is a function of method and facility, it is not possible to use a single correction factor to back-calculate to the nonstandardized value. A recent article by Stevens and collaborators (4 ) shows that efforts at back-calculation are not necessary. As part of a collaborative effort that pools data from 5504 individuals from a range of research 1 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. * Address correspondence to the author at: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Two Democracy Plaza, Room 645, 6707 Democracy Blvd., Bethesda, MD 20892-0001. Fax 301-480-3510; e-mail [email protected]. Received May 7, 2009; accepted June 25, 2009. Previously published online at DOI: 10.1373/clinchem.2009.127944 2 Nonstandard abbreviations: CKD, chronic kidney disease; eGFR, estimated GFR; MDRD, Modification of Diet in Renal Disease; IDMS, isotope-dilution mass spectrometry; CG, Cockcroft–Gault; FDA, US Food and Drug Administration; NKDEP, National Kidney Disease Education Program. Clinical Chemistry 55:9 1609–1611 (2009) Perspectives