Equations for Estimating Creatinine Clearance or GFR
Considerations and Variations of Creatinine Clearance
Cockcroft-Gault 1976^{1}
Particularly for renally dosing medications, the Cockcroft-Gault equation has been the long-standing gold standard for the estimation of creatinine clearance for decades. The original study was based on data from 249 male patients with stable renal function. The study used actual body weight, but mentioned that a correction factor of some kind should be used in patients with marked obesity or ascites.
$$
\\ CrCl =\frac{(140-Age)*(WeightInKg)}{72*SCr} *0.85\;(if\;female)
$$
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed as a follow-up to the MDRD equation in an attempt to be as accurate in describing renal function at lower GFR (less than 60 mL/min/1.73 m^{2}), but more accurate at a higher GFR. The CKD-EPI equation was developed and validated retrospectively in 8,254 patients from 10 studies. The study included all patients age > 20 years old who were not pregnant and did not have renal failure (defined as an eGFR < 15 mL/min/1.73 m^{2}). The data set included 45% women and 87% non-black patients.
$$
\\ GFR\;(mL/min/1.73 m^2) =\\ Black\;females,\;SCr\;\le\;0.7\;mg/dL:\\ 166 * (SCr/0.7)^{-0.329} * (0.993)^{Age}\\ Black\;females,\;SCr\;>\;0.7\;mg/dL:\\ 166 * (SCr/0.7)^{-1.209} * (0.993)^{Age}\\ Black\;males,\;SCr\;\le\;0.9\;mg/dL:\\ 163 * (SCr/0.9)^{-0.411} * (0.993)^{Age}\\ Black\;males,\;SCr\;>\;0.9\;mg/dL:\\ 163 * (SCr/0.9)^{-1.209} * (0.993)^{Age}\\ Non-black\;females,\;SCr\;\le\;0.7\;mg/dL:\\ 144 * (SCr/0.7)^{-0.329} * (0.993)^{Age}\\ Non-black\;females,\;SCr\;>\;0.7\;mg/dL:\\ 144 * (SCr/0.7)^{-1.209} * (0.993)^{Age}\\ Non-black\;males,\;SCr\;\le\;0.9\;mg/dL:\\ 141 * (SCr/0.9)^{-0.411} * (0.993)^{Age}\\ Non-black\;males,\;SCr\;>\;0.9\;mg/dL:\\ 141 * (SCr/0.9)^{-1.209} * (0.993)^{Age}
$$
Jelliffe 1973 (stable renal function)^{3}
DEPRECATED
Published as a "Letter to the Editor", the Jelliffe equation does not require a patient's height or weight because it describes renal function normalized to a body surface area of 1.73 m^{2}. While this was a landmark equation for its era, its use has become deprecated in favor of newer equations.
$$
\\ CrCl\;(mL/min*1.73\;m^2) = \frac{98 - 16*(\frac{Age-20}{20})}{SCr}\\ (CrCl\;is\;multiplied\;by\;0.9\;for\;female\;patients)
$$
Salazar-Corcoran 1988^{4}
DEPRECATED
This equation was specifically designed to measure creatinine clearance in obese patients (defined as a BMI ≥ 30 m^{2}). The equation is derived from a "fat free mass" equation and was shown to be superior to the Cockcroft-Gault and Jelliffe methods when using total body weight. Although interesting for historical reasons, the Salazar-Corcoran method has largely become deprecated in favor of the Cockcroft-Gault method with a body weight adjustment, such as the 40% adjustment factor equation.
$$
\\ CrCl\;(for\;men)\;=\\ \frac{(137-Age)*((0.285*WeightInKg) + (12.1*HeightInMeters^2) )}{51*SCr}\\ CrCl\;(for\;women)\;=\\ \frac{(146-Age)*((0.287*WeightInKg) + (9.74*HeightInMeters^2) )}{60*SCr}
$$
MDRD (four-variable)^{5}^{,}^{6}
DEPRECATED
The MDRD equation was originally developed in 1999^{7} as a six-variable equation, but has since been updated to a simpler, four-variable equation in two variations (to reflect the conventional and IDMS laboratory methods). The MDRD equation is more accurate than the Cockcroft-Gault method (particularly when using total body weight), but it is rarely used for drug dosing because most medications are validated using the Cockcroft-Gault method.
The MDRD equation was only studied in patients with renal dysfunction (GFR < 60 mL/min/1.73 m^{2}), and therefore it should not be used in patients with normal renal function. For this reason, the MDRD equation has become deprecated in favor of the CKD-EPI equation, which was developed similarly to the MDRD equation, but is able to accurately describe GFR in patients without renal dysfunction.
$$
\\ For\;IDMS-calibrated\;assays:\\ GFR\;(mL/min/1.73\;m^2) = 175 * (SCr)^{-1.154} * (Age)^{-0.203} \\ * (0.742\;if\;female) \\ * (1.210\;if\;African-American)\\ For\;non-IDMS\;assays:\\ GFR\;(mL/min/1.73\;m^2) = 186 * (SCr)^{-1.154} * (Age)^{-0.203} \\ * (0.742\;if\;female) \\ * (1.210\;if\;African-American)
$$
Equations for estimating unstable renal function
Most conventional, commonly used equations to estimate renal function require that patients have a stable renal function. Usually, this is defined as having two consecutive serum creatinine values, drawn at least 24 hours apart, within 20% of each other. Unfortunately, many hospitalized patients do not have stable renal function. For this reason, other equations have been developed to aid clinicians in estimating renal function for the purposes of drug dosing.
The two most common equations for estimating unstable renal function are the Jelliffe 1972^{8} and Chiou 1975^{9} methods.^{10} All of these equations lack the robust evidence of the equations for stable renal function and are poorly validated in a large group of patients. Generally speaking, these equations are developed using a one-compartment pharmacokinetic estimation model, and are less accurate when renal function is improving (rather than worsening).^{11} Although the data are not compelling, these are the best equations available for this patient population.
$$
\\ (Men)\;E^{SS} = IdealBW * (29.3 - (0.203*Age))\\ (Women)\;E^{SS} = IdealBW * (25.1 - (0.175*Age))\\ SCr_{avg} = (SCr1+SCr2)/2\\ E^{SS}_{corr} = E^{SS} * (1.035 - (0.0337*SCr_{avg}))\\ E = E^{SS}_{corr} - \frac{4*IdealBW*(SCr_2 - SCr_1)}{\Delta Time\;(days)}\\ CrCl (mL/min/1.73 m^2) = \frac{E}{14.4*SCr_{avg}}
$$
$$
\\ CrCl\;(for\;men) =\\ \frac{2*IdealBW*(28-(0.2*Age))}{SCr_1 + SCr_2} \\ + \frac{2*(0.6*IdealBW)*(SCr_1-SCr_2)}{(SCr_1 + SCr_2)*\Delta Time\;(hrs)}\\ - (0.0286*0.6*IdealBW)\\ CrCl\;(for\;women) =\\ \frac{2*IdealBW*(22.4-(0.16*Age))}{SCr_1 + SCr_2} \\ + \frac{2*(0.6*IdealBW)*(SCr_1-SCr_2)}{(SCr_1 + SCr_2)*\Delta Time\;(hrs)} \\ - (0.0286*0.6*IdealBW)
$$
Creatinine Clearance (CrCl) versus Glomerular Filtration Rate (GFR)
Creatinine clearance (CrCl) is an estimate of Glomerular Filtration Rate (GFR); however, CrCl is slightly higher than true GFR because creatinine is secreted by the proximal tubule (in addition to being filtered by the glomerulus). The additional proximal tubule secretion falsely elevates the CrCl estimate of GFR.^{12}
Equations that express GFR (such as MDRD and CKD-EPI) express GFR in mL/min/1.73 m^{2}. For the purposes of drug dosing or estimating GFR in patients with body size that is very different than average, GFR can be non-normalized using the following equation:^{12}
$$
\\ BSA = \sqrt{\frac{(HeightInCm * WeightInKg)}{3600}}
\\ GFR\;(mL/min) = GFR\;(mL/min/\;1.73 m^2) * BSA / 1.73
$$
Adjustment Factors for Female Gender
Many equations have an adjustment factor to account for the fact that female patients have less muscle mass, and therefore produce less creatinine. Historically, the Cockcroft-Gault and Jelliffe equations used an arbitrary value of 0.85 or 0.9 as a correction factor, but this value was largely based on empiric estimates with limited data. Fortunately, newer data have shown that this correction factor is actually relatively accurate, with an "optimal" correction factor between 0.84 and 0.88 being the most appropriate for female patients.^{13}
Adjustment for Obesity^{14}
Obesity has been a long-standing problem in the estimation of renal function. Serum creatinine production is approximated based on lean body weight because muscle tissue (not fat) is responsible for creatine production. Furthermore, a change in total body mass does not increase the size of the kidney (or GFR) proportionally. Equations that do not correct or adjust for obesity risk overestimation of true renal function.
While there is still significant debate regarding the optimal method of controlling for obesity, it appears that using the Cockcroft-Gault equation with a 40% adjustment is the most appropriate method. In one of the largest study on the topic to date of nearly 3000 overweight and obese patients, the following conclusions can be drawn:^{14}
- Actual body weight will significantly overestimate renal function
- Ideal body weight will significantly underestimate renal function
- The LBW2005 equation, while initially very promising,^{15}^{,}^{16} significantly underestimates renal function.
- For all classes of obesity (overweight, obese, and morbid obesity), the Cockcroft-Gault equation with a 40% adjustment proved to consistently offer the most accurate estimate of creatinine clearance (often within about 5 mL/min of accuracy)
There are equations that report GFR as a normalized value to body surface area (mL/min/1.73 m^{2}). While these may appear to circumvent the issue of obesity, these values need to be converted to a non-normalized GFR (mL/min) for the purposes of drug dosing. In the process of conversion, however, the non-normalized value will also overestimate GFR in obese patients.
Cockcroft-Gault 40% Obesity Adjustment
The most accurate equation for creatinine clearance in obese patients is the Cockcroft-Gault equation with a 40% adjustment factor.^{14} This equation is most appropriate for patients who are greater than 20-30% of their ideal body weight.^{17} In essence, this correction accounts for 40% of body mass above a patient's "ideal" body weight:
$$
\\ Adjusted\;weight = IdealBW + 0.4*(ActualBW-IdealBW)
$$
Ideal and Lean Body Weight (Devine 1974 and LBW2005)
Historically, the Devine 1974 equation^{18} has been used to estimate fat-free, ideal, or lean body weight (all terms generally meaning the same thing). This equation was not scientifically derived or validated,^{15} but is extensively used in medicine. A newer equation, called LBW2005^{19} may be a more promising estimation of lean body weight and has been derived and validated with actual patient data.
Rounding Creatinine in the Elderly
Some practitioners routinely round the serum creatinine of elderly patients (eg, > 60 years) to a value of 1 mg/dL in an effort to control for a reduced muscle mass. Intuitively, this practice does not make sense because rounding a serum creatinine of 0.3 mg/dL (230% increase) is much different than rounding a value of 0.8 mg/dL (25% increase). This practice becomes even more inconsistent when an elderly patient's serum creatinine is already above 1 mg/dL. The literature does not support this practice as it often results in an underestimation of true renal function.^{20}^{,}^{21} If any correction factor is used, it is likely that a percent adjustment, similar to underweight patients, would be the most appropriate; however, such a correction factor has not been studied in elderly patients.
Rounding Creatinine in Underweight Patients
In underweight patients, a low serum creatinine may be more reflective of a decrease in production rather than an increased rate of renal elimination. Similarly to elderly patients, clinicians may be tempted to round creatinine in underweight patients to account for less muscle mass; however, this practice is not supported by the literature.^{22} The most accurate method to control for underweight patients is to multiply the patient's Cockcroft-Gault value by an adjustment factor of 0.69 (regardless of whether the patient's serum creatinine is above or below 1 mg/dL). This correction factor was shown to be more precise and less bias than rounding or making no adjustment.
Medications that Modify Serum Creatinine
Because serum creatinine undergoes tubular secretion, any medications that interfere with this process will falsely elevate the patient's serum creatinine; however, this will not impact the patient's true GFR. The following medications have been shown to falsely elevate serum creatinine:^{12}^{,}^{20}^{,}^{23}
- Cefoxitin
- Cimetidine
- Cisplatin
- Flucytosine
- Trimethoprim
Populations who are Difficult to Estimate
Certain patient groups have dramatically different serum creatinine production or elimination compared to the normal patient population. The following groups are notoriously difficult to estimate true renal function:
- Amputation - Falsely low serum creatinine due to less production from muscle mass
- Burn injury - Increased GFR
- Cirrhosis - Falsely low serum creatinine due to less muscle mass and reduced hepatic conversion of creatine to creatinine
- Cystic fibrosis - Increased GFR
- Muscle disorders - Muscular dystrophy and other muscle disorders that can cause cachexia
- Pregnancy - Difficult to estimate lean body mass, increased GFR
- Unstable renal function - Equations used to estimate unstable renal function are very old and not validated in a large patient population
Impact of IDMS
There are primarily two laboratory methods for measuring serum creatinine: a number of conventional (older) methods (eg, alkaline picrate), and the newer IDMS method. The conventional methods have a positive bias (falsely elevated by up to 20%) because they detected non-creatinine chromagens.^{24} The conventional assay method is most susceptible to bias when serum creatinine is within the normal range. The NKDEP guidelines^{25} recommend that all laboratories convert their systems to use the newer, more accurate IDMS method. According to the NKDEP, almost all laboratories are expected to convert to the IDMS method by the end of 2010.
Note that this calculator automatically converts to and from IDMS as indicated based on the CrCl/GFR equation. All equations before the MDRD equation use non-IDMS creatinine values, the MDRD equation has two equations for either assay, and the CKD-EPI equation is only standardized for IDMS. The following equations are used to convert between IDMS and non-IDMS:^{26}
$$
\\ Conventional\;SCr\;(mg/dL) = (IDMS\;SCr)*1.065 + 0.067
\\ IDMS\;SCr\;(mg/dL) = ((Conventional\;SCr)-0.067)/1.065
$$
You may specify whether you are entering serum creatinine as an IDMS or 'conventional' assay by clicking the 'Advanced Settings' button beneath the 'Calculate' button.