Evaluating renal function for the purposes of drug dosing is a common task for clinical pharmacists, but a number of misconceptions have developed over the past forty years as the process of evaluating renal function has improved. The following are the top 10 facts that every clinician should know about creatinine clearance:
- Cockcroft-Gault is still the best equation for renally adjusting medications. Although the Cockcroft-Gault equation is less accurate than newer methods (MDRD and CKD-EPI) for estimating renal function, drug manufacturers typically use the older C-G method to determine renal adjustments of medications. Currently, the National Kidney Foundation recommends MDRD/CKD-EPI for evaluating the progression of renal function, and C-G for dosing medications.
- Don’t use the Salazar-Corcoran equation for obese patients. This equation was developed in the late 1980’s for the purposes of estimating renal function in obese (BMI ≥ 30 m2) patients. In the original manuscript, it was shown to be more accurate than the Cockcroft-Gault and Jelliffe equations using actual body weight, which is an unfair comparator. Later studies have shown that the Cockcroft-Gault equation using LBW2005 (a method of estimating a patient’s lean body weight) is the most accurate method.
- Don’t round serum creatinine to 1 mg/dL in elderly patients. In order to account for reduced muscle mass, it is a common practice for clinicians to round the serum creatinine of elderly patients to a flat 1 mg/dL. This practice has been studied in a number of papers, and has consistently been shown to be a poor correction. The practice is problematic because it doesn’t account for elderly patients with a creatinine above 1 mg/dL, and it doesn’t round on a percentage basis. The best practice is probably to reduce an elderly patient’s clearance by a flat percentage (perhaps 30%), although this method hasn’t been studied.
- MDRD is not an appropriate estimation method for patients with a GFR above 60 mL/min/1.73 m2. Because MDRD was developed in patients with renal dysfunction, it loses precision in patients with normal renal function. In fact, the newer CKD-EPI equation was specifically developed for this problem. CKD-EPI was designed to be as accurate as MDRD at lower renal function, but to have better precision in patients with normal renal function.
- IDMS has really messed things up. Isotope Dilution Mass Spectrometry (IDMS) is the newest assay for measuring serum creatinine. Older methods detected non-creatinine chromagens, which falsely elevated the amount of creatinine detected. This bias can be as high as 20%, and is especially problematic with a normal creatinine (closer to 1 mg/dL). While it’s great that the assay is more accurate, older methods of estimating renal function (specifically Cockcroft-Gault) will return a lower value with IDMS than with previous assay methods. It is possible to “convert” between older methods and the newer IDMS, but this practice increases the complexity and number of corrections required to calculate a creatinine clearance.
- You can (roughly) estimate creatinine clearance in patients with unstable renal function. All traditional equations (C-G, MDRD, CKD-EPI) require that a patient have a “stable” renal function (usually two similar values drawn more than 24 hours apart). Many hospitalized patients do not have a stable renal function, which means that these traditional equations are not appropriate for these patients. There are two methods to estimate “unstable” renal function (Jelliffe 1972 and Chiou 1975). These methods aren’t validated in a large number of patients and aren’t likely to be terribly accurate, but they are the only methods available.
- Creatinine clearance and GFR are different, but often (incorrectly) used interchangeably. Technically, creatinine clearance is a surrogate for GFR (glomerular filtration rate), but creatinine clearance slightly overestimates GFR. The kidney filters creatinine in the glomerulus (which is what GFR measures), but it also actively secrets creatinine in the proximal tubule (which should not be counted toward GFR). While the difference isn’t usually clinically relevant, it’s an important distinction.
- Certain medications can falsely elevate serum creatinine. The most pertinent medication that can increase serum creatinine is trimethoprim (a component of Bactrim or Septra) and cefoxitin (an antibiotic sometimes used for perioperative prophylaxis). These medications falsely increase creatinine because they inhibit the active secretion of creatinine in the proximal tubule, but it does not affect the glomerular filtration of creatinine.
- Cockcroft-Gault empirically picked a correction factor of 0.85 for female patients. The final C-G equation was developed using only male patients, so some may question the equation’s validity in female patients. Within the C-G manuscript, the authors mention that a correction factor of “0.85” for female gender is probably appropriate, but there was no direct evidence in the paper that this was an accurate correction. As it turns out, subsequent research has confirmed that a correction factor of about 0.85 is actually an appropriate adjustment.
- Please round your creatinine clearance and GFR. Even with the most accurate and precise equation (CKD-EPI), the median difference between actual and estimated GFR was as high as 3.5 mL/min/1.73 m2. Due to the imprecision in estimating creatinine clearance and GFR, it’s okay to round your renal estimation — even to the nearest 5 mL/min or 5 mL/min/1.73 m2. The fact of the matter is that these equations aren’t as accurate or precise as many would like to believe.
New ClinCalc – Creatinine Clearance and GFR Calculator
Also, hot off the press — a new calculator available at Creatinine Clearance and GFR Calculator. This calculator includes a variety of different equations, including Cockcroft-Gault, Jelliffe, Salazar-Corcoran, MDRD, and the new CKD-EPI. Also, it includes two equations for estimating renal function in patients with an unstable serum creatinine level.
Thank you for your concise view on this controversial topic.
1. Currently I feel that one should stick to the formula which was widely used in trials to document GFR for the drug of interest.
2. Your comment 'IDMS has messed up things'is not appropriate. IDMS has added clarity to measurement of creatinine. Most methods in biochemistry for measurment of creatinine are standardized to IDMS values.
Creatinine assays based on enzymatic assays do not suffer from interference with non-creatinine chromogens to any significant extent.
3. There are no clear guidelines for assessing clearance in AKI (acute kidney injury) patients.
4. I agree in part to your point no. 10 that 'formulae are not exact…….'but I fail to understand that as creatinine measurements have become more accurate and precise and the fact that the chemistry department keeps a control on quality, why would you prefer to introduce an increased uncertainty in results by rounding off?
Thank for the comments!
1. Ideally, the equation used in the drug trials should be listed on the package insert, although it usually is not (especially with older medications.
2. I should clarify — I love the fact that we’re using IDMS now, but it means that many of our older calculations are now inaccurate. Cockcroft-Gault has not been modified to account for IDMS, and most online calculators, kinetics textbooks, and mobile calculators do not account for IDMS.
3. Correct — there are a few equations for estimating clearance in AKI patients, but they are just that — estimates. They are not based on robust data and their limitations should be known.
4. The lack of precision doesn’t deal with the assay itself — the lack of precision comes from the equation to estimate renal function. Rounding the value is appropriate for the same reason that we round all values — a patient’s weight may be 71.035 kg, but we practically round the value because we recognize a lack of precision. Creatinine clearance is strictly a rough estimate and should be treated as such — providing clearances with tenth or hundreths of decimal accuracy is misleading to the accuracy of the estimate.