Creatinine Clearance

Creatinine clearance (CrCl) represents the volume of blood cleared of creatinine per unit time and is used to estimate the renal glomerular filtration rate (GFR). The GFR is the sum total of filtration rates of all functioning nephrons in the kidney and is the most accurate index of renal capacity; however, it cannot be measured directly. The most accurate test currently available to determine CrCl (and therefore GFR) is the timed, 24-hour urine for creatinine along with a concurrently drawn serum creatinine. These values are inserted into an equation using patient surface area (based on patient height and weight), with the resulting value reported in mL/minute. Although tubular secretion of creatinine results in an overestimation of the true GFR by 10% to 15%, the 24-hour study remains more accurate than simple serum creatinine alone in evaluating GFR, as serum creatinine is affected by muscle mass, age, gender, and tubular secretion (NKF, 2011).

An alternative to the cumbersome and inconvenient urine collection method is to estimate CrCl based on serum creatinine-based formulas. These formulas take into consideration gender, weight, and ethnicity to determine an estimated GFR (eGFR). While not as precise as the 24-hour urine method, eGFR equations improve upon the limitations of serum creatinine alone. Of the several formulas validated and endorsed by national renal groups to estimate GFR, the CockCroft-Gault equation is the one most often used to determine the need for medication adjustments in the clinical setting.

As outlined earlier in this text, the physiologic definition of ceatinine relates its serum or plasma level at any time to its urinary excretion rate at that point in time. This could be mathematically expressed as follows: $$Cl_{cr}=\frac{U_{cr(mg/dL)} \times V_{urine(mL)}}{S_{cr(mg/dL)}\times \Delta t_{(min)}}$$ GFR has invariably been equated with $Cl_{cr}$ since its estimation makes use of serum creatinine level and it accounts for all other patient's age and gender. Cockcroft-Gault [6] have devised alternative procedures that account for other physical characteristic of patients such as weight and height. $$Cl_{cr}=\left[\frac{(140-Age_{(yr)})\times Wt_{(kg)}}{72 \times S_{cr(ss)}}\right] \dots (M)$$ $$Cl_{cr}=0.85 \times \left[\frac{(140-Age_{(yr)})\times Wt_{(kg)}}{72 \times S_{cr(ss)}}\right] \dots (F)$$ Since $Cl_{cr}$ estimated by the above equation has been based on ideal body surface area $BSA = 1.73m^2$, its output must be normalized according to the specific BSA of the patient by a factor of $1.73m^2/BSA$.

Further adjustment is deemed necessary for obese subjects by inserting an adjusted IBW in the above equation according to the following formula: $$Adj.IBW_{(kg)}=IBW+0.4(TBW-IBW)$$ Another procedure suggested by Concoran-Salazar for the estimation of $Cl_{cr}$ in obese subjects whose weight is equivalent to 125% the IBW, in which case the following formula has been suggested: $$Cl_{cr}=\left[\frac{(137-Age_{(yr)})\times 0.285 \times Wt_{(kg)}+ 12.1\times H^2}{60 \times S_{cr}}\right] \dots (M)$$ $$Cl_{cr}=\left[\frac{(146-Age_{(yr)})\times 0.287 \times Wt_{(kg)}+ 9.74\times H^2}{60 \times S_{cr}}\right] \dots (F)$$ The above formula has been subject to criticism due to its failure to accurately account for creatinine clearance in obese individuals. Many clinicians prefer a 40% adjustment for the more robust Cochcroft-Gault equation.

In situations where the production of creatinine is unstable, Jellife & Choiu suggested two different procedures to estimate its clearance based on average levels of serum creatinine. It has been assumed that such levels would approximate SS creatinine levels which could be associated by its SS excretion $E_{SS}$.

By the early 1970s, Jellife and Jellife have suggested a formula to estimate creatinine clearance based on age, gender and serum creatinine levels. The following is depiction of this formula that has been cited by many sources. However, its direct implementation did not give reasonable values for creatinine clearance. $$Cl_{cr}=\frac{(98-16) \times (Age-20)/20}{S_{cr}}\text{, }mL/min/1.73m^2$$ Other sources have cited different equations which produced comparable values to other more recent equations. Notwithstanding, this method works reasonable for adults with normal muscle mas and has been superseded by more efficient formulas. $$Cl_{cr}=\frac{98 \times 0.8 \times (Age-20)}{S_{cr}}\dots (M)$$ $$Cl_{cr}=\frac{88 \times 0.7 \times (Age-20)}{S_{cr}}\dots (F) (mL/min/1.73m^2)$$ All equation used for the estimation of creatinine clearance were based on the assumption that the human body produces creatinine at a constant rate with time. However, when such condition is doubtful, new procedures have been independently suggested Jellife and Chiou. Both procedures take into account age IBM, age, gender and average serum creatinine over a specified period of time. Jelliffe & Jelliffe [11] have provided the following equations which have been used to estimate a SS serum level of creatinine which is corrected for IBW. $$E_{(SS)}=IBW_{kg}[29.3-(0.203 \times Age_{(yr)})]\dots (M)$$ $$E_{(SS)}=IBW_{kg}[29.3-(0.203 \times Age_{(yr)})]\dots (M)$$ $$E_{ss(corrected)}=E_{(SS)}[1.035-(0.0337 \times S_{cr(av)})]$$ $$E=E_{ss(corrected)}-\frac{4\times IBW_{(kg)}(S_{cr2}-S_{cr1})}{\Delta T \text{(days)}}$$ $$Cl_{cr(ss)}=\frac{E}{14.4\times S_{cr(av)}}\text{, }mL/min/1.73m^2$$

Measured Creatinine Clearance (CrCl)

$$CrCl_{[mL/min]}=Urine Cr_{[mg/dL]} \times Day'sUrineVolume_{[mL]}/SerumCr_{[mg/dL]}/1440$$ Many clinicians think that the procedure suggested by Chiou and his co-worker [12] for the estimation of creatinine clearance in cases were creatinine production is not stable is more reliable. These equations are provided as follows:

It must be noted that Jellife procedure has been deprecated in favor of the Chiou method.

Estimation of $Cl_{cr}$ in Pediatrics

Some empirical formulae [13] have been suggest for the estimation of creatinine clearance in pediatric population. The most commonly used procedure may be expressed as follows: $$Cl_{cr}=\frac{0.45 \times Height_{cm}}{S_{cr}}\text{, Infants up to 1 year of age, }(mL/min/1.73m^2)$$ $$Cl_{cr}=\frac{0.55 \times Height_{cm}}{S_{cr}}\text{, Children up 1 to 10 year of age, }(mL/min/1.73m^2)$$

CrCl by Jelliffe [22] - Obese Individuals

$$CrClNormalized_{[mL/min/1.73m^2]}=Sex\times \left( 98 - [0.8 \times (Age_{[Years old]}-20)]\right)/SerumCr_{[mg/dL]}$$ Equation parameters such as Sex, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 0.9, represent the values that will be used.

The Jelliffe formula represents a way to estimate CrCl. Because it is not weight-based, it may be preferred for use in obese subjects.

CrCl by Sanaka [23]

This author suggested an equation for elderly subject with aged between 60 - 92 years, with body mass between 24 and 61 kg $$CrCl_{[mL/min]}=\frac{Weight_{[kg]}\times \left[(MultiFactor \times PlasmaAlbumin_{[gm/dL]})+AddFactor\right]}{100\times SerumCr_{[mg/dL]}}$$ For females the Multi Factor is 13 and the Add Factor is 29. For males, the Multi Factor is 19 and the Add Factor is 32. However, its estimates may not be appropriate in patients with protein wasting states such as nephrotic syndrome.

Normal Values

Refer to testing laboratory for lab-specific normal values. Typical values:

Pediatrics: $70-140 mL/minute/1.73m^2$
Adult male: $85-125 mL/minute/1.73m^2$
Adult female: $75-115 mL/minute/1.73m^2$

Note: CrCl values generally decrease by $6.5 mL/min/1.73m^2$ per every 10 years after age 40.

Critical Values

Severe renal impairment: $15-29 mL/minute/1.73m^2$
End-stage renal impairment: $< 15 mL/minute/1.73m^2$

For drug dosing in the majority of patients, the difference in estimated GFR (eGFR) based on the two most widely used formulas, the Cockcroft-Gault equation and the MDRD Study equation, will not lead to a difference in drug dosages. Recent recommendations from the National Kidney Disease Education Program suggest that either value can be used to determine drug dosages (NKF, 2011).

CrCl by Cockcroft-Gault

$$CrCl_{[mL/min]}=Gender\times \left[ (140-Age_{[yr]})/(SerumCr_{[mg/dL]})\right]\times Weight_{[kg]}/72$$ Equation parameters such as Sex, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. 0.85, represent the values that will be used.

The default unit of measure for weight is kilograms. Please verify that the correct unit of measure has been selected.

This Equation provides an estimate of the creatinine clearance (Cr Clear) if the plasma creatinine concentration is stable. Weight is the estimated lean body weight.

CrCl by Cockcroft-Gault with IBW [24] - Obese Subjects

$$CrCl_{[mL/min]}=\left[ (140-Age_{[yr]})/(Weight_{[kg]}CrCl_{[mL/min]}/(SerumCr_{[mg/dL]}\times 72))\right]\times CrCl_{mL/min}Sex$$ This calculator is not appropriate for dialysis patients or for pediatric patients. (IBW represents the calculated ideal body weight).

The Cockcroft-Gault Equation estimates creatinine clearance and uses IBW unless the actual weight is less than the IBW in which case, the actual weight is used.

The $CrCl Sex$ term is 0.85 for females and 1 for males.

Advantages and Limitation of Different Methods

It is evident that the above given methods for estimating creatinine clearance have advantages and limitation. Accordingly. It is the sole responsibility of users to determine the best method suited to the clinical situation being dealt with. Merits and shortcomings of these methods are summarised in the table provided hereunder:

MRDR Study: Modification of Diet in Renal Disease Study equation
CKD-EPI: The Chronic Kidney Disease Epidemiology Collaboration equation
Formula calculators available at: www.kidney.org/professionals/kdoqi/gfr_calculator.cfm

FormulaAdvantagesLimitations

Cockcroft-Gault	Extensively reviewed in the drug study literature and widely used for drug dosage recommendations Easily calculated ${[(140-age) \times weight] / (72 \times S_{cr})} x 0.85$ if female	Does not take into consideration body surface area in an era of increasing obesity Overestimates CrCl by 10% to15% Does not correct for ethnicity Only for > 18 years old
MDRD Study	Normalized to body surface area Includes consideration due to ethnicity Updated in 2005 for use with standardized serum creatinine assays Superior when renal function is moderate to severely reduced	Complicated formula requiring access to computer-based applications Tends to underestimate GFR in healthy individuals Less accurate for $eGFR > 60 mL/min/1.73m^2$ Has not been validated for < 18, > 85 years old, pregnancy
CKE-EPI	Normalized to body surface area Includes consideration due to ethnicity Superior when GFR is normal or only mildly reduced Only for use with standardized creatinine assays	Complicated formula requiring access to computer-based applications Has not been validated for <18 years old, pregnancy, and certain ethnic subgroups (Hispanics)
Schwartz	For use in those < 18 years old Includes consideration for child’s height and muscle mass, which varies by age Updated in 2009 for use with standardized serum creatinine assays