|
Timed urine collections are associated with significant collection errors,
due to improper timing and missed samples. Timed overnight collections or shorter
timed daytime collections may reduce the inconvenience of a 24-hour collection, but
are still associated with collection errors.
Creatinine clearance equations
An accurate, reliable and unbiased method for calculating creatinine clearance from
serum creatinine is much sought after by clinicians. Dozens of methods for estimating
creatinine clearance have been published, but no single method is ideal for all
patients. Furthermore, much controversy exists as to which method is best for a
particular patient group.
In adults, the Cockcroft and Gault equation has become the defacto
standard despite many documented problems.5,6,7,8 C&G produces consistent
results in patients of average size and build, with stable renal function and a SCr
less than 3 mg%. However, it is problematic in others.
The C&G equation was derived from a group of lean males, bringing into question the
validity of this method in obese patients. The
Salazar and Corcoran
equation was derived from an obese patient population, and may be more appropriate for
this group.16
In patients with unstable renal function, Jelliffe's multi step
method may be more accurate. This method corrects for rising SCr and for chronic
renal failure.15
The MDRD method
was derived from a study of a large diverse patient population having a wide range of
renal function. The MDRD equations have also been validated in a separate, equally large
and diverse group. Therefore, some feel that MDRD is the most accurate CLCR method
overall.26, 27 Nevertheless, for dosing purposes, NKDEP does not recommend using
the MDRD study equation at this time because the clinical impact on drug dose adjustment has
not been compared to current practice. Pharmacists should continue to use their current drug
dosing methods.28
Please see our online creatinine clearance calculator to compare the results from these various
adult creatinine clearance equations:
In children 12 and older, the Cockcroft and Gault equation gives a reasonably accurate
estimate of creatinine clearance. For younger children, infants and neonates, no method
of estimating CLCR is reliable.
The Swartz equation
is the standard equation for young children, however, the results are not consistent enough
to be used for pk modeling.20
Dosing guidelines
Dosage adjustment guidelines which are based on creatinine clearance have been
published.3,4 Manufacturers are now required by FDA to provide dosage
guidelines for patients with decreased creatinine clearance.
A dosage regimen may be adjusted either by lowering the dose or prolonging the
dosage interval. The dosage reduction method is recommended for those drugs for
which a relatively constant blood level is desired, e.g., beta-lactam antibiotics.
The interval extension method is recommended for those drugs whose efficacy is
related to the peak level, e.g., fluoroquinolone antibiotics.
II. Monitoring Parameters
The following screening criteria may be used to identify patients who are
at risk of impaired renal function:
- Age 65 years and over
- Elevated serum creatinine
III. Precautions
- The following conditions may falsely elevate serum creatinine,
thereby falsely decreasing the creatinine clearance.
- Dehydration
- Drugs:
- Cephalosporins
- Cimetidine
- Trimethoprim-sulfa
- The following conditions may falsely decrease serum creatinine,
thereby falsely elevating the creatinine clearance.
- Muscular diseases (muscular dystrophy, polymyositis, rhabdomyolysis)
- Small muscle mass (due to atropy or amputation, cachexia or malnutrition)
- Liver disease (cirrhosis)
- Other precautions
Obesity
Cockcroft & Gault derived their equation from a group of 296 males, all within
10% of LBW, leading many to question the validity of this method in obese
patients. Studies have generally found that use of TBW (total body weight)
tends to over-estimate CLCR in obese patients, while use of LBW (lean body
weight) tends to under-estimate CLCR.17 Various weight correction factors have been
proposed, each has their proponents and detractors:
- Use of LBW plus 20 to 40% of the excess weight.
- Normalizing to 72 kg.
- Normalizing to BSA of 1.73 M2
An alternative for this group is the
Salazar and Corcoran
method which was derived from an obese patient population.16
Elderly
The Cockcroft & Gault equation tends to over-estimate CLCR in the elderly.12
Therefore, an empiric "correction" commonly employed is to round up the serum
creatinine to 1.0 mg% in elderly patients. However, most studies have found
this to be an inappropriate practice which under-estimates true CLCR.13
Very low serum creatinine
Use of a very low serum creatinine (0.5 mg% or less) in the C&G equation leads to a
falsely elevated CLCR. Therefore, many practitioners designate 0.7 mg% as
the minimum SCr which should be used in the equation.
Rising serum creatinine
If the serum creatinine is rising, it is likely not at steady-state. SCr may
require one week to stabilize following a decrease in renal function. Conversely,
after renal function improves to normal, the shift of SCr to its new steady-state
level occurs rapidly, since the new half life is now quite short. Thus, the
probability that SCr may not be at steady-state is much greater when SCr is
rising, than when it is falling. Jelliffe's multi step
method, which corrects for rising SCr, is more accurate than C&G in patients with
unstable renal function.15
Women
As stated above, C&G derived their equation from a group of men, the 0.85 factor
for women was added afterwards, to correct for the smaller muscle mass of females.
One study found that a 0.9 factor for women may be more accurate.10
Diet
Serum creatinine will be affected by dietary extremes. Patients who are following
an unusual vegetarian diet may have a lower SCr than expected. A diet excessively
rich in red meat will lead to the reverse error.
IV. Program procedure
After selecting the drug, click on the Prospective dosing tab to
view the dosing table. The program asks for the current dosage.
This is necessary if recommending a dosage adjustment, otherwise,
if determining an initial dosage, just leave blank. Next type in
your dosage recommendation.
For some drugs a one-compartment model may be selected. If a one compartment
model is selected, the program calculates an ideal dose, based on the dosing
weight and creatinine clearance. After the user enters a practical dose and
interval, the program calculates estimated steady state peak and trough levels.
If an MIC is entered, PK/PD parameters will be calculated. For more information
on this subject, please see this page:
V. Renal drug dosing flow chart

VI. Pharmacokinetic formulas
The drug models are not hard-coded into the program. The parameters are
found in the drug model database and are fully user-edit able. You can
tailor each drug model to fit your patient population, or you can create
your own models.
- Calculate lean body weight (LBW)21
LBW (Males) = 50 + (2.3 x Height in inches over 5 feet)
LBW (Females) = 45.5 + (2.3 x Height in inches over 5 feet)
- Calculate adjusted body weight (ABW)
Because creatinine is a by-product of muscle metabolism, excess weight
in the form of adipose tissue, does not significantly affect the production
of creatinine. Therefore, lean body weight or an adjusted body weight is used
for CLCR calculations.
ABW = LBW + [CF x (TBW - LBW)]
. . . where CF = correction factor (usually 20 to 40%)
. . . where WT = patient's total weight
- Calculate body surface area (BSA)22
BSA = 0.007184 x (HT0.725 + WT 0.425)
. . . where HT = height in centimeters
. . . WT = weight in kilograms
- Jelliffe Multi-step method15
- Estimate urinary creatinine excretion rate (E)
E (males) = LBW x (29.305 -[0.203 x (age)])
E (females) = LBW x (25.3 -[0.18 x (age)])
- Correct E for nonrenal creatinine excretion in chronic renal failure
E = E x [1.035 - 0.0377(SCr)]
. . . where SCr is the latest serum creatinine OR if SCr is rising, the average SCr
- Correct E for rising serum creatinine
E = E - [4 x LBW x (SCr1-SCr2)] / D
. . . where LBW = lean body weight in kilograms
. . . SCr1= the latest serum creatinine
. . . SCr2= the earlier serum creatinine
. . . D = the number of days between
- Calculate normalized creatinine clearance (CLCR)
CLCR/1.73 M2 = (E * 0.12) / (SCr * BSA)
. . . where BSA is body surface area in M2
- Cockcroft and Gault equation23
CLCR Males = ABW(140 - Age) / (SCr x 72)
CLCR Females = 85% of male value
. . . where SCr is the most recent serum creatinine.
. . . ABW = adjusted body weight
- Calculate dosage
Option 1 - Dosing table
Dosage tables are derived from either the FDA approved package insert,
Bennett's tables, AHFS Drug Information, or Critical Care Pharmacotherapy.
An example of a dosing guideline from the package insert is shown in Table 1.
An example of a dosing table is shown in Table 2.3
Table 1. Manufacturer's dosage recommendation for Neurontin®
CLCR
(mL/min)
|
Total Daily Dose
(mg/day)
|
Dose Regimen (mg)
|
>/=60
|
900-3600
|
300 TID
|
400 TID
|
600 TID
|
800 TID
|
1200 TID
|
>30-59
|
400-1400
|
200 BID
|
300 BID
|
400 BID
|
500 BID
|
700 BID
|
>15-29
|
200-700
|
200 QD
|
300 QD
|
400 QD
|
500 QD
|
700 QD
|
15a
|
100-300
|
100 QD
|
125 QD
|
150 QD
|
200 QD
|
300 QD
|
a
For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
|
Table 2. Dosage adjustment for renal impairment
Drug
|
Method
|
CLCR > 50ml/min
|
CLCR 10 to 50ml/min
|
CLCR < 10ml/min
|
Acyclovir
|
I
|
5mg/kg Q 8 hr
|
5mg/kg Q 12 hr
|
5mg/kg Q 24 hr
|
Ampicillin
|
D, I
|
1-2 g Q 6 hr
|
0.5 g Q 6-8 hr
|
0.5-1g Q 12 hr
|
Aztreonam
|
D, I
|
1-2 g Q 6-8 hr
|
0.5-1g Q 8 hr
|
0.5-1g Q 12 hr
|
Cefazolin
|
D, I
|
1-2 g Q 6-8 hr
|
1-2 q Q 12-24 hr
|
1 g Q 48 hr
|
Cefotetan
|
D, I
|
1-2 g Q 12 hr
|
1-2 g Q 12-24 hr
|
0.5 - 1g Q 24 hr
|
Option 2 - One compartment model
If parameters are available, a one compartment model may be employed.
Model parameters for common antibiotics are listed in Table 3.25
Table 3. One-compartment model parameters
Drug
| Target peak/trough
| A
| B
| C
|
Acyclovir
| 40/10
| 0.035
| 0.002
| 0.217
|
Ampicillin
| 50/ 5
| 0.058
| 0.0064
| 0.26
|
Azlocillin
| 250/25
| 0.116
| 0.0058
| 0.16
|
Aztreonam
| 100/10
| 0.116
| 0.0023
| 0.143
|
Carbenicillin
| 200/20
| 0.046
| 0.0042
| 0.346
|
Cefamandole
| 60/ 6
| 0.043
| 0.0065
| 0.216
|
Cefazolin
| 120/20
| 0.032
| 0.0026
| 0.15
|
Cefonicid
| 150/25
| 0.014
| 0.0016
| 0.10
|
Ceforanide
| 120/20
| 0.023
| 0.0021
| 0.132
|
Cefotaxime
| 80/ 4
| 0.069
| 0.0056
| 0.159
|
Cefotetan
| 120/20
| 0.02
| 0.00178
| 0.125
|
Cefoxitin
| 60/ 6
| 0.035
| 0.0066
| 0.216
|
Ceftazidime
| 60/ 6
| 0.028
| 0.0034
| 0.237
|
Ceftizoxime
| 60/ 6
| 0.028
| 0.0046
| 0.229
|
Cefuroxime
| 60/ 8
| 0.041
| 0.0051
| 0.174
|
Cephalothin
| 50/ 5
| 0.06
| 0.0114
| 0.26
|
Cephaparin
| 50/ 5
| 0.06
| 0.0092
| 0.24
|
Cephradine
| 50/ 5
| 0.06
| 0.0065
| 0.26
|
Imipenem
| 40/ 1
| 0.173
| 0.0052
| 0.162
|
Methicillin
| 40/ 4
| 0.173
| 0.0075
| 0.305
|
Mezlocillin
| 250/25
| 0.173
| 0.0052
| 0.155
|
Piperacillin
| 250/25
| 0.173
| 0.0052
| 0.156
|
Ticarcillin
| 200/20
| 0.043
| 0.0053
| 0.336
|
- Calculate elimination rate constant (Kel) using A & B from Table 2.
Kel = A + (CLCR x B)
. . . where CLCR = Creatinine clearance
- Calculate dosing weight (DW)
DW = LBW + CF x (ABW-LBW)
. . . where ABW = patient's true weight
. . . LBW = lean body weight
. . . CF = correction factor
- Calculate volume of distribution (Vd) using C from Table 2.
Vd = DW * C
- Calculate ideal dosing interval (tau)
tau = tinf + -1 / Kel x ln (Cpmin/Cpmax)
. . . where Cpmin = Target trough
. . . Cpmax = Target peak
- Calculate ideal maintenance doses
MD = Kel x Vd x Cpmax x tinf x (1 - e-Kel x tau / 1 - e-Kel x tinf)
- User selects practical dosage and interval
- Calculate expected peak & trough levels
Peak = MD / tinf x Vd x Kel x (1 - e-Kel x tinf / 1 - e-Kel x tau)
Trough = Peak * e-Kel x (tau - tinf)
The one feature that the RxKinetics family of pk programs have in common is
the ability to edit the default drug models. You can edit any model to better
fit your patient population, you can even add your own 1-compartment models
for any drug and for multiple patient populations, a "Swiss army knife" for
clinical pharmacokinetics if you will. Please see the following tutorial for
a basic overview of how to create a one compartment model:
VII. Bibliography
- Lipman AG.
Drug Therapy Considerations in the Renally Compromised Geriatric Patient.
Consultant Pharmacist 1987;Supp B:3-7.
- Caldwell JR.
Alterations in Renal Function in the Elderly Population: Implications for Medication Prescribing.
Consultant Pharmacist 1987;Supp B:3-7.
- Chernow, Bart
Pocket Book of Critical Care Pharmacotherapy 1st edition.
Lippincott, Williams & Wilkins, 1995.
- Aronoff George R, et al.
Drug Prescribing in Renal Failure.
Philadelphia, PA. ACP, 1999.
- Lott RS, Hayton WL.
Estimation of Creatinine Clearance from Serum Creatinine Concentration - a review.
Drug Intell Clin Pharm 1978;12:140-150.
- Sawyer WT, et al.
Variables Affecting Creatinine Clearance Prediction.
Am J Hosp Pharm 1983;40:2175-80.
- Rhodes PJ, et al.
Evaluation of Eight Methods for Estimating Creatinine Clearance in Men.
Clin Pharm. 1987;6:399-406.
- Chow MS, Schweizer R.
Estimation of Creatinine Clearance in Patients with Unstable Serum Creatinine Concentrations: Comparison of Multiple Methods.
Drug Intell Clin Pharm 1985;19:385-390.
- Hull JH, et al.
Influence of range of renal function and liver disease on predictability of creatinine clearance.
Clin Pharmacol Ther. 1981 Apr;29(4):516-21.
[ PubMed ]
- Canaday BR, et al.
Fractional Adjustment of Predicted Creatinine Clearance in Females.
Am J Hosp Pharm 1984;41:1842-3.
[ PubMed ]
- Melamed AJ, Vanamee P.
Estimating creatinine clearance in patients with cancer.
Hosp Pharm 1988;23:898-901.
- Drusano GL, et al.
Commonly used methods of estimating creatinine clearance are inadequate for elderly debilitated nursing home patients.
J Am Geriatr Soc. 1988 May;36(5):437-41.
[ PubMed ]
- Smythe M, Hoffman J, Kizy K, Dmuchowski C.
Estimating creatinine clearance in elderly patients with low serum creatinine concentrations.
Am J Hosp Pharm. 1994 Jan 15;51(2):198-204.
[ PubMed ]
- Lau AH, et al.
Estimation of creatinine clearance in malnourished patients.
Clin Pharm 1988:7;62-65.
[ PubMed ]
- Jelliffe RW, Jelliffe SM.
Estimation of creatinine clearance in patients with unstable renal function. (revised).
Originally published: A computer program for estimation of creatinine clearance from unstable serum creatinine concentration.
Math Biosci. 14:17-24 (June) 1972.
- Salazar DE, Corcoran GB.
Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass.
Am J Med. 1988 Jun;84(6):1053-60.
[ PubMed ]
- Dionne RE, Bauer LA, Gibson GA, Griffen WO Jr, Blouin RA.
Estimating creatinine clearance in morbidity obese patients.
Am J Hosp Pharm. 1981 Jun;38(6):841-4.
[ PubMed ]
- Paap CM, Nahata MC.
Prospective evaluation of ten methods for estimating creatinine clearance in children with varying degrees of renal dysfunction.
J Clin Pharm Ther. 1995 Apr;20(2):67-73.
[ PubMed ]
- Hernandez de Acevedo L, Johnson CE.
Estimation of creatinine clearance in children: comparison of six methods.
Clin Pharm. 1982 Mar-Apr;1(2):158-61.
[ PubMed ]
- Pierrat A, Gravier E, Saunders C, Caira MV, Ait-Djafer Z, Legras B, Mallie JP.
Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and MDRD formulas.
Kidney Int. 2003 Oct;64(4):1425-36.
[ PubMed ]
- Devine Ben.
Gentamicin therapy.
Drug Intell Clin Pharm 1974;8:650-6.
- DuBois D, DuBois EF.
A formula to estimate the approximate surface area if height and weight be known.
Arch Intern Medicine. 1916; 17:863-71.
- Cockroft D.W., Gault M.H.
Prediction of creatinine clearance from serum creatinine.
Nephron. 1976;16(1):31-41.
[ PubMed ]
- Pai MP, Paloucek FP.
The origin of the "ideal" body weight equations.
Ann Pharmacother. 2000 Sep;34(9):1066-9.
[ PubMed ]
- Zaske D, Lesar T. "Other Anti-Infective Agents" in
A Textbook for the Clinical Application of Therapeutic Drug Monitoring, Taylor and Caviness (Ed).
Abbott Laboratories, Irving, TX. 1986.
- Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D.
A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group.
Ann Intern Med 130:461-470, 1999.
[ PubMed ]
- Levey AS, Greene T, Kusek JW, Beck GJ.
A simplified equation to predict glomerular filtration rate from serum creatinine.
J Am Soc Nephrol 11:A0828, 2000 (abstr)
- Gary L. Myers, W. Greg Miller, Josef Coresh, et al. Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory
Working Group of the National Kidney Disease Education Program. Clinical Chemistry 2006;52(1):5-18.
[ PDF ]
[ Summary ]
VIII. Recommended Reading
- Aronoff George R, et al: Drug Prescribing in Renal Failure. Philadelphia, PA. ACP, 1999.
- Bauer, Larry A. Applied Clinical Pharmacokinetics. McGraw-Hill. 2001.
- Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics 3rd edition. San Francisco, CA. Applied Therapeutics, 1992.
- Chernow, Bart Pocket Book of Critical Care Pharmacotherapy 1st edition. Lippincott, Williams & Wilkins, 1995.
IX. Additional WWW Resouces
|