**Information on the Use of the**

**Modification of Diet in Renal Disease Equation to Estimate Glomerular
Filtration Rate**

**and the Cockcroft-Gault Equation to Estimate Creatinine Clearance for
Medication Dosing in Patients with Kidney Dysfunction**

VHA Pharmacy Benefits Management Services and Medical Advisory Panel,

Renal Field Advisory Committee, and Pathology and Laboratory Medicine
Services

**Summary**

This document has been developed to clarify the role of the estimated
glomerular filtration rate (eGFR) that is being routinely calculated per
the Modification of Diet in Renal Disease (MDRD) equation and reported
in the laboratory package to determine the patient's level of kidney
function, and the estimated creatinine clearance (CrCl) using the
Cockcroft-Gault equation that is used to determine appropriate
medication doses based on the patient's kidney function. 

As recommended by the National Kidney Foundation^1^ and the VHA/DoD
Clinical Practice Guideline (CPG) for Management of Chronic Kidney
Disease (CKD) in Primary Care,^2^ the eGFR should be used when
determining the level of a patient's kidney function. The VHA Pathology
and Laboratory Medicine Services, in conjunction with Medicine and
Surgery, have established the eGFR as the primary measure for kidney
function; this is automatically measured through a VistA patch that has
been implemented throughout the VA.

The estimated CrCl using the Cockcroft-Gault equation is primarily used
to determine the dose and regimen for a medication based on kidney
function and is the most frequent basis for dosing recommendations in
the product information approved by the FDA and in pharmacy references
that include dosing adjustments based on CrCl.  

Therefore, the eGFR should be routinely used for estimating the level of
the patient's kidney function (at eGFR levels less than 60 ml/min/1.73
m^2^) whereas the estimated CrCl should continue to be used when
determining the most appropriate dose of a medication for the patient,
unless stated otherwise.

**Recommendations (per VA/DoD CKD CPG)^2^**

1.  The severity of CKD should be classified based on the level of the
    eGFR

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1.  Kidney function in patients with CKD should be assessed by
    formula-based eGFR, preferably using the 4-variable MDRD equation

2.  Serum creatinine alone should not be used as a measure of kidney
    function

3.  In clinical laboratories without the ability to automatically
    incorporate race into the MDRD calculation, adjusted values for race
    should be determined

4.  There is no need to collect 24-hour urine samples to measure CrCl

**Estimated CrCl (Cockcroft-Gault Equation)**

The estimated CrCl using the Cockcroft-Gault equation as follows:

CrCl (ml/min) = \[(140-age) x weight (kg)\]/(72 x sCr)\] x 0.85 if
female

Due to the difficulty and cost involved in the direct measurement of
GFR, it is more practical to use an estimation of GFR. Serum creatinine
(sCr) is used as a marker for GFR; however, since it is dependent on
muscle mass (e.g., a patient with low muscle mass and significant kidney
impairment may present with a normal sCr) and may be influenced by other
factors such as diet, it is not recommended to be used to determine the
patient's level of kidney function. The Cockcroft-Gault equation takes
into consideration sCr in addition to the patient's age, weight, and
gender. In patients who are obese, it is recommended that lean or ideal
body weight be used since the equation was not corrected for this
condition.^3^ The Cockcroft-Gault equation was developed based on a
population of nearly 250 primarily male Canadian veterans using a
measured 24-creatinine clearance.^3,4^ Since clearance depends on the
plasma concentration as well as the excretion rate, and excretion is a
measure of GFR and tubular secretion, clearance becomes more inaccurate
as filtration rates decrease, resulting in an overestimation of GFR. In
the majority of patients, the eGFR using the MDRD equation (described
below) and the estimated CrCl using the Cockcroft-Gault equation should
not result in a difference in drug dosing; however, the Cockcroft-Gault
equation to estimate the CrCl has been the most widely used to determine
appropriate drug dosing based on the patient's kidney function. Since
the majority of manufacturer's drug labeling approved by the FDA
includes dosing recommendations based on the estimated CrCl using the
Cockcroft-Gault equation and the medication's pharmacokinetics, it is
therefore recommended that this equation be used to determine the
patient's dose and regimen, unless otherwise specified. The eGFR should
not be routinely used to determine medication dose and regimen unless
specifically recommended since patients may not receive an adequate dose
or an adjustment in dose when it would have been recommended according
to the estimated CrCl.^4-6^

**eGFR (MDRD Equation)**

The eGFR is reported using the 4-variable MDRD (MDRD4) equation as
follows:

eGFR (ml/min/1.73 m^2^)= 186 x \[S~Cr~\]^--1.154^ x \[age\]^--0.203^ x
\[0.742 if female\] x \[1.210\] if black

(Note: laboratories using an isotopic dilution mass spectrometry (IDMS)
traceable measurement of sCr should use the following formula: eGFR =
175 x \[S~Cr~\]^--1.154^ x \[age\]^--0.203^ x \[0.742 if female\] x
\[1.210\] if black)

More recently, the MDRD equation has been employed as a measurement of
kidney function^1,2,7^ and may be more accurate than the estimated CrCl
for patients with CKD and GFR \< 60 ml/min/1.73 m^2^.^8^ The 6-variable
MDRD (MDRD6) equation was derived from the MDRD population that included
over 1600 patients with nondiabetic CKD and a mean GFR of
40[+]{.underline}21 ml/min/1.73 m^2^, with a direct measurement of GFR
using iothalamate. In addition to age, gender and sCr, the MDRD6
equation includes blood urea nitrogen, albumin and race.^7^
Subsequently, the MDRD4 equation was found to be similar in sensitivity
and specificity to the MDRD6 in patients with iothalamate measured GFR
in patients with GFR \< 60 ml/min/1.73 m^2^.^9^ The MDRD equation is not
recommended for use at eGFR levels above 60 ml/min/1.73 m^2^.^1,2,10,11^
An advantage of the eGFR as calculated by the MDRD equation is that it
does not require height or weight measurements and is adjusted for body
surface area. An evaluation of the MDRD equation based on pooled data
for variables including age, gender, race, diabetes, transplant, and
body mass index (BMI) found there to be only slight variability in the
eGFR at levels \< 60 ml/min/1.73 m^2^, although the median difference
for Asian patients was nearly 11%. The median variability for patients
with a BMI \< 20 was -4.7% and 4.0% for a BMI \>25. At an eGFR
[\>]{.underline} 60 ml/min/1.73 m^2^, the percent difference was greater
for nearly all variables measured.^11^ It is recommended that clinicians
be aware of the limitations of the eGFR, especially in patients with
values near 60 ml/min/1.73 m^2^ (and that the MDRD equation may
underestimate GFR at levels between 60 and 120 ml/min/1.73 m^2^ and
overestimate at eGFR levels \> 120 ml/min/1.73 m^2^)^11^ or who have the
potential for reduced creatinine production as in low muscle mass,
malnutrition, low protein intake, and chronic disease, and in patients
with extremes in age, body size, obesity, paraplegia or quadriplegia.^1^
It should be noted that these methods used to estimate kidney function
should only be used if sCr is in steady state, not in cases of acute
renal failure.

In conclusion, the eGFR should be routinely used for estimating the
level of the patient's kidney function whereas the estimated CrCl should
continue to be used when determining the most appropriate dose of a
medication for the patient, unless stated otherwise.

**References**

1.  Levey AS, Coresh J, Balk E, et al. National Kidney Foundation
    practice guidelines for chronic kidney disease: evaluation,
    classification, and stratification. Ann Intern Med 2003;139:137-47.

2.  Clinical practice guideline for management of chronic kidney disease
    in primary care. Washington, DC: VA/DoD Evidence-Based Clinical
    Practice Guideline Working Group, Veterans Health Administration,
    Department of Veterans Affairs, and Health Affairs, Department of
    Defense, Update 2007. Office of Quality and Performance publication
    10Q-CPG/CKD-07.

3.  Cockcroft DW, Gault MH. Prediction of creatinine clearance from
    serum creatinine. Nephron 1976;16:31-41.

4.  Dowling TC. Controversies in assessing kidney function. In:
    Nephrology I. Pharmacotherapy Self-Assessment Program-VI, Book 2.
    6^th^ ed. Lenexa, KS: ACCP; 2007:1-13.

5.  Wargo KA, Elland III EH, Hamm W, English TM, Phillippe HM.
    Comparison of the Modification of Diet in Renal Disease and
    Cockcroft-Gault equations for antimicrobial adjustments. Ann
    Pharmacother 2006;40:1248-53.

6.  Gill J, Malyuk R, Djurdjev O, Levin A. Use of GFR equations to
    adjust drug doses in an elderly multi-ethnic group -- a cautionary
    tale. Nephrol Dial Transplant 2007;22:2894-9.

7.  Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, for the
    Modification of Diet in Renal Disease Study Group. A more accurate
    method to estimate glomerular filtration rate from serum creatinine:
    a new prediction equation. Ann Intern Med 1999;130:461-70.

8.  Poggio ED, Wang X, Greene T, Van Lente F, Hall PM. Performance of
    the Modification of Diet in Renal Disease and Cockcroft-Gault
    equations in the estimation of GFR in health and in chronic kidney
    disease. J Am Soc Nephrol 2005;16:459-66.

9.  Levey AS, Coresh J, Greene T, et al. Using standardized serum
    creatinine values in the Modification of Diet in Renal Disease study
    equation for estimating glomerular filtration rate. Ann Intern Med
    2006;145:247-54.

10. Bostom AG, Kronenberg F, Ritz. Predictive performance of renal
    function equations for patients with chronic kidney disease and
    normal serum creatinine levels. J Am Soc Nephrol 2002;13:2140-4.

11. Stevens LA, Coresh J, Feldman HI, et al. Evaluation of the
    Modification of Diet in Renal Disease study equation in a large
    diverse population. J Am Soc Nephrol 2007;18:2749-57.