The Importance of Accurately Estimating Renal Function When Determining Dosing

Eric A. Dietrich, PharmD, BCPS
Kyle Davis, PharmD, BCPS
Volume 56 - Issue 3 - March 2016

Renal function plays a significant role in the selection and dosing of numerous medications, including antibiotics. Although inulin may be the best measure of glomerular filtration rate (GFR), the measurement of serum creatinine is much more feasible and thus has become the standard of care when assessing renal function.

Specifically, GFR can be estimated by calculating creatinine clearance (CrCl) using the Cockcroft-Gault equation, which uses a patient’s age in years, body weight in kg, serum creatinine level in mg/dL, and sex to estimate the CrCl: ([140 – age] × body weight / 72 × serum creatinine) × 0.85 (if female). This equation has been validated and is used in most pharmacokinetic studies to establish medication dosing recommendations.1 While this equation is widely used, it does have limitations. Specifically, the equation was validated in nonobese patients. It has been theorized that using adjusted body weight (ABW) may better estimate GFR in obese patients.

Additionally, elderly patients have smaller muscle mass, which contributes to lower creatinine values, which in turn can lead to overestimation of GFR when using the Cockcroft-Gault equation. In an attempt to avoid such overestimation, many providers round up the serum creatinine to 1.0 mg/dL in elderly patients if the baseline value is less than 1.0 mg/dL. While such practices have become mainstream, are they appropriate?

Case Report

A 77-year-old white woman with a  history of hypertension, hyperlipidemia, and osteoarthritis presents with a 3-day history of dysuria and flank pain. She weighs 52 kg, is 157.5 cm tall, and her serum creatinine level is 0.7 mg/dL. Results of urinalysis are positive for a urinary tract infection. You diagnose cystitis and send a urine culture. You wish to start nitrofurantoin empirically because of a history of intolerance to sulfa drugs (nausea, swelling, rash), ciprofloxacin (itching, rash), and cephalexin (rash). Knowing that nitrofurantoin has a GFR dosing restriction, an accurate estimation of her renal function is important. Therefore, you estimate renal function using the Cockcroft-Gault equation:
([140 – 77] × 52 / 72 × 0.7) × 0.85 = 55 mL/min. Should 1.0 have been used instead to estimate CrCl?

The Evidence

The use of ABW in obese patients and the rounding of serum creatinine values in elderly patients when using the Cockcroft-Gault equation has not been thoroughly studied. Winter and colleagues2 evaluated the use of these strategies of GFR calculation in a retrospective review of 3678 hospitalized patients with at least 2 serum creatinine values and who underwent 24-hour urine collection. They compared the measured 24-hour CrCl with the estimated CrCl using the Cockcroft-Gault equation. Regarding dosing weights, the authors found that in nonobese patients, ideal body weight (IBW) provided a more accurate estimation of GFR than did actual body weight. In underweight patients, actual body weight yielded the best measure of GFR. Additionally, they found the use of an ABW calculation by a factor of 0.4 (ABW = IBW + 0.4 × [actual body weight – IBW]) to be the most accurate way of estimating renal function in overweight, obese, and morbidly obese patients. Finally, in patients aged 65 years or older, the use of measured serum creatinine in the Cockcroft-Gault equation better estimated GFR than using a standard of 1.0 mg/dL.

Clinical Application

Estimating renal function is essential for accurate drug dosing in patients with renal dysfunction. Most medications are dosed based on the Cockcroft-Gault equation, which relies heavily on the serum creatinine value. 

While many clinicians adjust the serum creatinine up to 1.0 mg/dL in elderly patients with a serum creatinine level of less than 1.0 mg/dL, the available evidence suggests that this practice should be avoided. This adjustment likely overestimates the degree of renal dysfunction (and estimates a falsely low CrCl) and can lead to lower doses being administered than are needed. 

While these lower doses likely lower the chances of adverse effects occurring with most medications, certain medication classes such as antibiotics or antiepileptics require a specific concentration for efficacy, and therefore the risk of clinical failure is increased due to inadequate concentrations as a result of the medication being underdosed.

If the goal is to minimize the chances of adverse effects, correction of the serum creatinine may be considered, but when specific target concentrations are needed, the available evidence suggests that using a patient’s true serum creatinine value is the most reliable method for accurately estimating CrCl and determining the appropriate dose according to the patient’s renal function.

In our patient’s case, using a serum creatinine value of 1.0 mg/dL in the Cockcroft-Gault equation yields and estimated CrCl of 39 mL/min. Conversely, using her true serum creatinine value of 0.7 mg/dL yields a CrCl of 55 mL/min.

Outcome of the Case

Based on the available evidence, we would use 0.7 mg/dL for determining our patient’s creatinine clearance, which yields an estimated CrCl of 55 mL/min using the Cockcroft-Gault equation. Using 1.0 mg/dL instead of 0.7 mg/dL would not improve the accuracy of the estimation of her true renal function and instead likely falsely overestimates the degree of her renal dysfunction. Because a target concentration is needed for the efficacy of nitrofurantoin, using a falsely low CrCl value could lead to underdosing of the antibiotic and an increased chance of clinical failure.

She is not obese—her body mass index is 21 kg/m2—so her ideal body weight can be used (55 kg), and her estimated CrCl is 58 mL/min using the Cockcroft-Gault equation, which does not significantly alter her estimated CrCl.

However, there is a suggestion that the antibiotic nitrofurantoin should not be used in patients with a CrCl lower than 60 mL/min. Next month’s column will discuss the clinical scenario of assessment of renal function and the use of nitrofurantoin.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville, and he completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

  1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266.
  2. Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy. 2012; 32(7):604-612.