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

Abstract

Objectives: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population.

Design: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010.

Subjects: A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute.

Measurements and main results: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively.

Conclusion: The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.

Keywords: BLSA; GFR; creatinine clearance; drug safety; geriatrics; glomerular filtration rate.

Figure 1

Comparison of kidney function estimation methods. Data are mean ± 95% confidence interval. Measured CLcr = creatinine clearance obtained from a 24-hour urine collection; CG = creatinine clearance estimated by using the Cockcroft-Gault equation; MDRD = glomerular filtration rate estimated by using the Modification of Diet in Renal Disease equation; CKD-EPI = glomerular filtration rate estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. *p<0.001 vs measured CLcr, CG, and CKD-EPI; ^#p<0.001 vs. measured CLcr, CG, and MDRD, using paired analyses.

Figure 2

Bland and Altman plots showing the within-person differences between the estimated creatinine clearance obtained by using the Cockcroft-Gault equation (CG) and measured 24-hour creatinine clearance (mCLcr) (panel A), estimated glomerular filtration rate obtained by using the Modification of Diet in Renal Disease equation (MDRD) and mCLcr (panel B), estimated glomerular filtration rate obtained by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and mCLcr (panel C). The solid line indicates mean difference, and the dashed line indicates limits of agreement.

Figure 3

Drug dose discordance rates. Panel A shows the discordance rates for the Modification of Diet in Renal Disease equation (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with manufacturer-recommended dosing based on estimated creatinine clearance. Panel B illustrates the median discordance rates for four drugs requiring dosage adjustment at the lower range of creatinine clearance for MDRD and CKD-EPI.