Glomerular filtration rate equations overestimate creatinine clearance in older individuals enrolled in the Baltimore Longitudinal Study on Aging: impact on renal drug dosing.

Age-related decline in kidney function is seen in a substantial portion of the older population.1 Nearly 40% of adults aged 70 years or older have an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2.2 Most of these older adults have no obvious source of loss of kidney function other than physiologic aging. Accurate estimation of kidney function is especially important in this population (13% of the US population), as these older adults consume nearly 34% of all prescription drugs,3 and many of these drugs have elimination that is dependent on the kidneys. Estimating kidney function by using an equation that is based on serum creatinine concentration (Scr) instead of directly measuring kidney function can lead to substantial dosing errors in some populations. Older adults can have normal or minimally increased Scr in the presence of significantly reduced renal function due to their reduced muscle mass. Failure to account for reduced glomerular filtration rate (GFR) can lead to excessive drug doses due to prolongation of the drug’s half-life, especially in older adults.4,5 Hanlon et al. recently reported that nearly 12% of the residents in a Veterans Affairs nursing home were prescribed at least one incorrect dosage based on kidney function; excessive drug doses were the most common medication error reported in this study.6 Collecting urine for determination of measured 24-hour creatinine clearance (mClcr) is the gold standard measurement of kidney function in pharmacokinetic studies conducted during drug development. However, this method is time consuming and logistically difficult, and is rarely done in clinical settings. For almost 50 years, kidney function has been estimated using the Cockcroft-Gault (CG) equation, which estimates creatinine clearance based on Scr, age, sex, and weight.7 A recent survey of new drug applications submitted to the FDA from 1998–2007 showed that the CG equation was specifically mentioned as the basis for calculating dosage adjustments in patients with renal impairment for 25% of the drugs reviewed.8 Other equations have been proposed for estimating renal function, including the Modification of Diet in Renal Disease (MDRD) equation9 and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.10 It is important to note that the CG equation was designed to estimate creatinine clearance, whereas the MDRD and CKD-EPI equations estimate GFR. The GFR is the volume of blood delivered to Bowman’s capsule per unit of time and is regulated by afferent and efferent tone in the vessels before and after the capsule. The GFR can be directly measured by inulin or iothalamate clearance. Creatinine clearance, on the other hand, is affected by GFR and postcapsule secretion and is directly measured in a 24-hour urine collection. Although the MDRD and CKD-EPI equations were not designed to estimate creatinine clearance, in clinical practice they are often used interchangeably with the CG equation. The values obtained from the three equations are used as if they all estimate creatinine clearance, and the numeric values obtained from the three equations are used without adjustment when considering changing the dosage of a medication to account for kidney function. A recent study showed that using estimated GFR (eGFR) values obtained from the MDRD equation instead of the traditional CG equation led to higher doses and increased risk of bleeding for enoxaparin and eptifibatide11, as well as excessive doses of dofetilide, which has been associated with cardiac conduction abnormalities such as changes in the QTc interval and the life-threatening arrhythmia, torsade de pointes.12 A recent review of FDA-approved drug dose labels showed that the most common estimating equation used in renal drug dose algorithms is the CG equation.8 Clinicians often use the MDRD and CKD-EPI equations to calculate drug dosages since clinical laboratories routinely report eGFR values obtained when Scr tests are ordered. The National Kidney Disease Education Program (NKDEP) recently recommended that eGFR (MDRD equation) and the CG equation can be used interchangeably for the purpose of drug dosing13, a recommendation that is controversial and has not been rigorously evaluated in older patients. In older individuals with very low Scr values (<1.0 mg/dL) and reduced muscle mass, a common practice of replacing Scr with an arbitrary value, such as 1.0 mg/dL, for use in the CG equation, has been reported but not fully evaluated.14–16 The objectives of the current study were to evaluate performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. Specifically, we identified the bias and precision of the CG, MDRD, and CKD-EPI equations relative to mClcr in older subjects, evaluated differences in dose calculations between the CG and MDRD equations for commonly prescribed drugs, and evaluated the use of an arbitrary Scr value (1.0 mg/dL) in the CG equation in patients with very low Scr values (< 1.0 mg/dl).