Moving Beyond Cockcroft-Gault When Estimating Kidney Function

For decades, the Cockcroft-Gault formula has been the main tool pharmacists use to estimate kidney function using creatinine clearance (CrCl) and determine appropriate medication dosing. It has been the basis for clinicians' dose adjustments based on renal function and labeling. However, growing evidence has shown that it is often inaccurate.

The Cockcroft–Gault formula was developed before standardized creatinine assays, relied on data from a small group of White men, and has limitations when applied across diverse patient groups. It frequently overestimates kidney function, and differences in how clinicians adjust for age, sex, and body weight lead to inconsistent results. It also affects nonrenal function–related increases in serum creatinine, such as those caused by medications like trimethoprim (Primsol; Aytu BioPharma), imatinib (Gleevec; Novartis), and amiodarone (Pacerone; Upsher-Smith Laboratories). The accurate assessment of renal function ensures efficacy, safety, and stewardship.

A clinical debate is ongoing to move pharmacists toward race-free eGFR equations, such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. Editorial consensus from the National Kidney Foundation and American College of Clinical Pharmacy has called for transitioning from CrCl to race-free eGFR as the preferred renal function estimate for medication-related decision-making.^1,2 These equations better reflect true kidney function, avoid the problematic use of race as a variable, and are being incorporated into electronic health records (EHRs). The FDA issued guidance to the industry, recommending eGFR over the Cockcroft-Gault formula for pharmacokinetic evaluation in patients with impaired renal function.² Several recent expert consensus documents have highlighted this debate, bringing it to the forefront of pharmacy practice.^1,2

One recent study supports this change. The study by Dickerson et al evaluated the accuracy of commonly used creatinine-based kidney function estimation equations in critically ill trauma patients with presumed normal baseline renal function. Using measured 24-hour urinary creatinine clearance as the reference standard, the investigators compared estimates derived from the Cockcroft–Gault and CKD-EPI equations. Both equations underestimated true renal clearance in this population; however, CKD-EPI demonstrated closer agreement with measured creatinine clearance. These findings underscore the limitations of relying on traditional CrCl-based estimates in critically ill patients, and suggest that exclusive dependence on the Cockcroft–Gault formula may increase the risk of subtherapeutic medication dosing. Overall, this study adds to the growing body of evidence supporting a transition toward eGFR-based methods for informing drug-dosing decisions in modern pharmacy practice.³ Dosing per CrCl may put patients at risk for subtherapeutic dosing of many medications. This has been theorized and estimated in a few trials regarding β-lactam dosing in patients with septic shock.^4,5

A recent study by Aldardeer et al evaluated the clinical impact of early vs delayed renal dose adjustment of antipseudomonal β-lactam antibiotics in critically ill patients with sepsis-associated acute kidney injury (AKI). In this prospective, multicenter, observational cohort study, adult patients with sepsis and AKI in the intensive care unit who received an initial full β-lactam dose were stratified based on whether renal dose reduction occurred within 24 hours (early adjustment) or after 24 hours (late adjustment) of sepsis recognition. Delayed dose adjustment was associated with a significantly lower risk of in-hospital mortality compared with early adjustment, even after multivariable adjustment for illness severity and confounders. Patients in the late adjustment group also demonstrated higher rates of AKI recovery and resolution of kidney injury within 48 hours. Aggressive early renal dose reduction of β-lactams in sepsis-associated AKI may contribute to subtherapeutic exposure during a critical treatment window and support a more cautious, trajectory-based approach to renal dosing in the early phase of severe infection.⁴

Despite this push toward eGFR-based dosing, many EHRs continue to focus on CrCl for pharmacists. With these new trials, calls to action, and a growing number of organizations pushing for change, a major movement is underway, shaking the foundations of how pharmacists determine renal dosing. This movement toward race-free, body-surface-area–adjusted eGFR may not only improve accuracy but also promote greater consistency in medication dosing. Studies have shown that using race-free CKD-EPI eGFR may improve the prediction of kidney clearance, reduce toxicity, and increase the effectiveness of medications primarily cleared by the kidneys, such as antibiotics.^6-8 This transition will require awareness and education for pharmacists and other clinicians, but it will likely represent an important step forward in patient care.

As evidence continues to mount, the limitations of relying solely on the Cockcroft–Gault equation for renal dosing decisions are becoming increasingly difficult to ignore. Transitioning toward race-free eGFR-based estimates represents a meaningful evolution in pharmacy practice—one that aligns with contemporary laboratory standards, regulatory guidance, and the need for equitable, accurate, and consistent patient care. Pharmacists are uniquely positioned to lead this transition by critically evaluating renal function estimates, interpreting emerging evidence, and advocating for appropriate dosing strategies within interprofessional teams. In practice, pharmacists can help address EHR limitations, educate colleagues on the strengths and limitations of different renal equations, and apply clinical judgment, particularly in high-risk settings.

Although implementation will require system-level changes and ongoing education, pharmacist leadership will be essential to ensuring these tools are used thoughtfully and effectively. By embracing more accurate kidney function estimates, pharmacists can better balance efficacy and safety, avoid subtherapeutic dosing during critical illness, and strengthen antimicrobial stewardship, reinforcing their role as medication experts at the center of patient care.

REFERENCES

1. Bzowyckyj AS, St. Peter WL. A call to action: transitioning from Cockcroft-Gault estimated creatinine clearance to race-free estimated glomerular filtration rate. J Am Coll Clin Pharm. 2025;8(5):324-326. doi:10.1002/jac5.70018

2. St. Peter WL, Bzowyckyj AS, Anderson-Haag T, et al; National Kidney Foundation Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions. Moving forward from Cockcroft-Gault creatinine clearance to race-free estimated glomerular filtration rate to improve medication-related decision-making in adults across healthcare settings: a consensus of the National Kidney Foundation Workgroup for Implementation of Race-Free eGFR-Based Medication-Related Decisions. Am J Health Syst Pharm. 2025;82(12):644-659. doi:10.1093/ajhp/zxae317

3. Dickerson RN, Adams DS, Farrar JE, et al. Estimating measured creatinine clearance for critically ill trauma patients with presumed normal kidney function. Am J Health Syst Pharm. 2025;82(11):e498-e506. doi:10.1093/ajhp/zxaf028

4. Aldardeer NF, Alshreef MM, Alharbi EA, et al. Early versus late antipseudomonal β-lactam antibiotic dose adjustment in critically ill sepsis patients with acute kidney injury: a prospective observational cohort study. Open Forum Infect Dis. 2024;11(3):ofae059. doi:10.1093/ofid/ofae059

5. Taccone FS, Laterre PF, Dugernier T, et al. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126. doi:10.1186/cc9091

6. Delanaye P, Björk J, Courbebaisse M, et al. Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment. Br J Clin Pharmacol. 2022;88(5):2118-2127. doi:10.1111/bcp.15132

7. Mirkov S, Scuderi C, Lloyd J, et al. Estimation of kidney function for medication dosing in adult patients with chronic kidney disease: a practice update. J Pharm Pract Res. 2024;54(1):94-106. doi:10.1002/jppr.1884

8. Barreto EF, Chang J, Rule AD, et al. Impact of various estimated glomerular filtration rate equations on the pharmacokinetics of meropenem in critically ill adults. Crit Care Explor. 2023;5(12):e1011. doi:10.1097/CCE.0000000000001011