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AOPXXX10.1177/1060028013507699BrownAnnals of Pharmacotherapy

Letters

Response to Letter to the Editor

TO THE EDITOR: Donald Cockcroft and M. Henry Gault could scarcely have imagined in 1976 the profound impact their equation would have on the practice of medicine, let alone the drug dosing controversies it would propagate. Masselink, Lalla, and I weighed in (no pun intended) on the controversy by describing several comprehensive studies conducted within the past 10 years that were designed to resolve the weight controversies of the Cockcroft–Gault equation once and for all—but to no avail. The most recent addition to the debate, a letter to the editor of Annals,1 articulates valid arguments for eliminating weight from the equation, thus generating an estimate of creatinine clearance that is “corrected” to a standardized body weight of 72 kg. Cockcroft and Gault included weight in their linear regression, producing an uncorrected creatinine clearance in mL/min.2 They noted, however, that “by chance,” an average male weight of 72 kg would cancel out weight from the equation. I generally agree with the comments made by the authors of the letter with one exception—the final statement that calls for further investigation comparing the Cockcroft– Gault equation with a weight factor and without. The 2011 meta-analysis of Wilhelm and Kale-Pradhan3 included 5 trials with patients in a “no body weight” category, although the units were mL/min rather than mL/min/72 kg. Their meta-analysis found the “no body weight” approach to be more accurate that either actual body weight or total body weight, and as accurate as adjusted body weight. Nevertheless, whether using adjusted body weight or no body weight in the equation, 2 potential sources of error remain. First, Dowling et al4 described that there are inconsistent, and in some cases, incomplete renal dosing recommendations for many drugs, some of which fail to identify whether weight (or which form of weight) was applied to the Cockcroft–Gault equation in the original dosing study. One cannot assume that the creatinine clearance values in a drug dosing chart are intended to be corrected to a standard body weight unless clearly specified, and if guidelines define a creatinine clearance range in mL/min, it would be inappropriate to apply a weight-corrected patient value. The best approach is to match units when possible, whether mL/ min, mL/min/70 kg, or mL/min/1.73 m2. Second, one cannot ignore that creatinine is an endogenously produced substance, the serum concentration of which is not solely dependent on renal elimination. Variations in body composition, based on proportion of muscle mass to total body mass, affect the relative rate of production of creatinine, thereby altering the quantitative relationship between serum creatinine and creatinine clearance. The Cockcroft–Gault equation is a

Annals of Pharmacotherapy 47(11) 1590­ © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013507699 aop.sagepub.com

linear regression formula derived from a specific 1970s cohort. The more a patient deviates in body composition from the original cohort, the greater the potential for error. The growing prevalence of obesity in our population is an increasingly confounding factor for the Cockcroft–Gault equation—one that could be exacerbated by eliminating the weight factor. Eliminating weight might be a suitable approach for some patients, but not others. The same can be said for any of the Cockcroft–Gault weight approaches currently applied in clinical practice. No single method is universally appropriate. That is why basing drug dosing decisions on a functional range of estimated creatinine clearance seems to make the most sense. Richardson5 said it best with a quote from Aristotle, “It is the mark of an educated mind to rest satisfied with the degree of precision which the nature of the subject admits and not to seek exactness where only an approximation is possible.” The estimation of creatinine clearance for drug dosing purposes remains an inexact science. Clinically sound approximation, which strategically accounts for the inherent imprecision of the Cockcroft–Gault equation, is a more prudent course of action than a perpetual quest for a level of precision that simply does not exist. Daniel L. Brown, PharmD Palm Beach Atlantic University, West Palm Beach, FL, USA [email protected] Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Ahern J. Remembering the past: creatinine clearance and drug dosage adjustment. (letter) Ann Pharmacother 2013;47:15881589. 2. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. 3. Wilhelm SM, Kale-Pradhan PB. Estimating creatinine clearance: a meta-analysis. Pharmacotherapy. 2011;31:658-664. 4. Dowling TC, Matzke GR, Murphy JE, Burckart GJ. Evaluation of renal drug dosing: prescribing information and clinical pharmacist approaches. Pharmacotherapy. 2010;30:776-786. 5. Richardson MM. Precision versus approximation: the trade off in assessing kidney function and drug dosing. Pharmacotherapy. 2010;30:758-761.

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Response to letter to the editor.

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