Corey Diamond, PharmD
A study published in Pharmacotherapy on November 19, 2022, challenges the long-held notion that renal function should be adjusted based on race.
After running a pharmacokinetic population analysis on a large group of patients, researchers found “race” (more specifically, those self-identified as African American) was an insignificant covariate in determining the clearance of both gentamicin and tobramycin.
Additionally, a secondary finding by Pai and colleagues suggests that indexation of renal clearance estimates to a body surface area (BSA) of 1.73 m2—such as is often done in estimated glomerular filtration rate (eGFR) calculations—may make eGFR equations less accurate.
Pharmacokinetic analysis design
Manjunath and colleagues conducted a retrospective cohort analysis using pharmacokinetic data from DATADIRECT, a clinical database maintained by the University of Michigan. Their analysis included data from over 2,900 adult patients from 2009 to 2022 who received gentamicin or tobramycin.
The authors derived a highly accurate base pharmacokinetic model for aminoglycoside clearance using their patient data. They then attempted to fit that model to several different renal function clearance equations—including the Cockcroft-Gault equation (eCLcr), the 2009 CKD-EPI eGFRcr equation, and the 2021 CKD-EPI eGFRcr equation—in order to determine how well these equations correlated with the aminoglycoside clearances of the patients in the study. Additionally, as a secondary investigation, the authors modified the 2009 and 2021 CKD-EPI renal function estimate equations to include or exclude BSA—indexing to 1.73 m2—to see if it strengthened or weakened correlation with their model.
Ultimately, the authors attempted to fit 5 different equations to their base model: the Cockcroft-Gault equation, the 2009 CKD-EPI equation with BSA, the 2009 CKD-EPI equation without BSA, the 2021 CKD-EPI equation with BSA, and the 2021 CKD-EPI equation without BSA. The Akaike information criterion—a mathematical method for evaluating how well a model fits the data—was used to measure which renal function equation fit the aminoglycoside clearance model the best.
Overall, the analyses demonstrated that renal clearance equations that included race as a covariate (such as the 2009 CKD-EPI equation) fit almost identically to the pharmacokinetic population model compared to renal clearance equations that did not incorporate race (Cockcroft-Gault and the 2021 CKD-EPI equation).
Additionally, the modified CKD-EPI eGFR equations, that deindexed BSA, fit the aminoglycoside clearance model more strongly than the equations that used BSA as a covariate.
Why the change?
Adjusting eGFR based on certain racial ancestry has been, until recently, a standard of practice in the United States. This was, in part, due to previous studies showing an increased average serum creatinine value of 10% to 20% in self-identified African Americans patients compared with American Caucasian patients. Thus, the 2009 CKD-EPI eGFR equation included a 1.159 correction factor to prevent underestimating eGFR in the African American population.
However, the 2009 CKD-EPI eGFR equation has received increasing scrutiny over the past decade due to concern over race being a social construct rather than a biological one. Ultimately, unease in the medical field over ignoring diversity and contributing to systemic racism culminated in 2020, resulting in the American Society of Nephrology and the National Kidney Foundation helping to publish a new CKD-EPI eGFR equation in 2021 that removed race as a covariate.
In addition to the use of race, another issue with CKD-EPI eGFR is its indexing of BSA to 1.73 m2. Historically, 1.73 m2 was considered normal BSA for humans and has been used to index a variety of medical equations as a means of normalizing several physiological variables. However, this too, has recently been scrutinized. Due to the obesity epidemic, normal BSA in Americans is currently about 2 m2 and the arbitrary role of BSA in eGFR calculations may be contributing to unnecessary errors in renal predictions.
Results and rationale
“Our study does not support race as a relevant covariate either alone or in equations that estimate GFR for determining aminoglycoside CL,” concluded the authors in their article. They wrote that the 2021 CKD-EPI eGFR equation offers similar precision to the 2009 CKD-EPI eGFR equation for the estimation of gentamicin and tobramycin clearance.
“The 2021 CKD-EPI eGFR equation without race and BSA indexation should be evaluated as a potential standard model for drug dosing across kidney function in drug development,” wrote the study authors. ■
Editor’s note: This article is part of Pharmacy Today’s ongoing coverage of structural racism.