In this episode I’ll discuss a long time pet peeve of mine – the Cockcroft Gault formula can be used to predict – not calculate – creatinine clearance.

40 years after it’s publication, the Cockcroft Gault formula remains the most appropriate method of estimating kidney function for the purpose of renal dose adjustment of medications. I use the formula dozens of times each day.

Even though in 2010 the FDA changed it’s guidance for industry to allow using MDRD estimated GFR for drug dosing, I’m not aware of any medications that use the MDRD formula in place of Cockcroft-Gault for renal dose adjustment.

The Cockcroft-Gault formula is: (((140-age)*weight in kg)/(serum creatinine*72))*0.85 if female

The full text of the 1976 study by Cockcroft and Gault is required reading for my pharmacy students and residents. I haven’t found it available for free online so you’ll need to check with your medical librarian to get a copy.

Rapid, non-invasive bedside prediction of kidney function is essential for patient care and medication dosing. 24 hour urine creatinine clearance calculations are impractical for many reasons including being time-consuming and error-prone.

History

Donald W. Cockcroft is an asthmatologist who teaches at the University of Saskatchewan.

In 1973 he was finishing a 3 month nephrology rotation with M. Henry Gault. As part of his nephrology rotation, he completed a research project to verify the accuracy of a nomogram that predicted creatinine clearance based on age, weight, and serum creatinine. Cockcroft and Gault were reviewing the data and the negative linear correlation between age and creatinine clearance when Cockcroft realized this could be turned into a formula to predict creatinine clearance. In a 1992 interview Cockcroft stated:

This formula yields results which are in reasonably good agreement with measurements obtained from 24-hour urine collections. It thus allows a quick and easy assessment of creatinine clearance as long as serum creatinine (thus renal function) is in a steady state.

I find that the qualifiers from the original study “as long as serum creatinine is in a steady state” are often forgotten. Because it is presented as a formula, it can be tempting to think of use of the formula as “calculating” creatinine clearance.

Study Characteristics

Let’s examine the characteristics of the patients in the original Cockcroft Gault study:

Creatinine at steady state

All patients had two 24 hour urine creatinine measurements that did not differ by more than 20%. This means all patients had steady-state serum creatinine and renal function.

Male

The 249 patients evaluated in the study were male. The idea of reducing the value from the formula by 15% in female patients is “expert opinion”.

Body weight

Total body weight was used in the study, but essentially all patients were very close to their ideal body weight.

Age

The range of patient ages in the study was 18-92, but 75% of the patients in the study were less than 70 years old.

With all of these caveats, the equation predicted creatinine clearance to +/- 17% of the actual creatinine clearance. This means if the formula predicts a creatine clearance of 50 mL/min, the actual value is between 42 and 58 – which could easily straddle a decision point for reducing a medication dose due to renal insufficiency.

Summary

To summarize, the Cockcroft-Gault equation was validated primarily in male patients under the age of 70, with stable renal function who were close to their ideal body weight. Adjustments to the weight used in the formula, rounding the serum creatinine, and reducing the value empirically for female patients are based on expert opinion and not validated in the original study.

Application to clinical practice

How many of your hospitalized patients match the characteristics of the patients in the original Cockcroft-Gault study?

Most of my ICU patients would not have met the inclusion criteria for the study based on their creatinine not being at steady state.

The Cockcroft-Gault formula remains the best at determining the need for dose adjustment in renal insufficiency, but how should it be applied to patients?

I think an assessment of the risk vs benefit of adjusting a medication for renal insufficiency should be made. I discussed making patient focused risk:benefit assessments in episode 11.

Many critically ill patients are not at steady state renal function. In such patients I will take the trend in serum creatinine and combine that with the results of the Cockcroft-Gault formula.

For example, in a patient whose creatinine has increased from 1 to 1.5 mg/dL and Cockcroft-Gault estimates a creatine clearance of 40 mL/min I will think “The creatinine clearance is worse than 40 mL/min” since the patient’s creatinine is trending up.

Likewise in a patient whose creatinine has decreased from 2 to 1.5 mg/dL and Cockcroft-Gault estimates a creatine clearance of 40 mL/min I will think “The creatinine clearance is better than 40 mL/min” since the patient’s creatinine is trending down.

There are two reasons to adjust a medication based on renal insufficiency:

1. To prevent toxicity

2. To save money

In a critically ill patient, I usually err on the side of not reducing a medication dose unless the goal of reducing the dose is to prevent toxicity.

Take for example piperacillin-tazobactam in a patient with sepsis and acute renal insufficiency. The risk of dosing high for 24 hours is lower than the risk of dosing low. So I’ll often wait to renally adjust the dose until the 2nd serum creatinine result is back and I can get a better idea of how the patient’s kidneys are functioning.

If the goal of reducing the medication dose is to prevent toxicity, then I usually err on the side of reducing the dose or monitoring when possible.

Take for example vancomycin in the same patient with sepsis and acute renal insufficiency. Since vancomcyin is nephrotoxic, I may give single doses and check levels before the next dose to avoid making assumptions that could lead to further kidney injury.

I’ve created a simple, mobile responsive creatinine clearance estimator at pharmacyjoe.com/clcr based on the Cockcroft-Gault formula. I haven’t included multiple equation variations or body weight adjustments because in the end, it is just an estimate and should be treated as such.

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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