Transcript Estimation of GFR using Cockcroft-Gault Equation

Effect of Renal Disease
on
Pharmacokinetics
Dr Mohammad Issa Saleh
Introduction
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Most water-soluble drugs are eliminated
unchanged to some extent by the kidney.
Drug metabolites that were made more water
soluble via oxidation or conjugation are
typically removed by renal elimination
The nephron is the functional unit of the
kidney that is responsible for waste product
removal from the body and also eliminates
drug molecules
Introduction
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Unbound drug molecules that
are relatively small are filtered at
the glomerulus. Glomerular
filtration is the primary
elimination route for many
medications
Drugs can be actively secreted
into the urine, and this process
usually takes place in the
proximal tubules
Tubular secretion is an active
process conducted by relatively
specific carriers or pumps that
move the drug from blood
vessels in close proximity to the
nephron into the proximal tubule
Introduction
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Some medications may be
reabsorbed from the urine back
into the blood by the kidney
Reabsorption is usually a
passive process and requires a
degree of lipid solubility for the
drug molecule. Thus, tubular
reabsorption is influenced by the
pH of the urine, the pKa of the
drug molecule, and the resulting
extent of molecular ionization
Compounds that are not ionized
in the urine are more lipid
soluble, better able to pass
through lipid membranes, and
more prone to renal tubular
reabsorption
Effect of Renal Disease on
Drug Absorption
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The bioavailability of most drugs that have
been studied in renal failure has not been
altered.
In chronic renal failure, D-xylose, a marker for
small intestinal absorptive function:
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Absorption was slower (0.555 h-1 vs. 1.03 h-1)
Less complete (48.6% vs. 69.4%)
Bioavailability decreased for furosemide and
pindolol in renal failure
Bioavailability in Renal
Disease
Unchanged
Increased
Cimetidine
Dextropropoxyphene
Ciprofloxacin
Erythromycin
Codeine
Propranolol
Digoxin
Tacrolimus
Effect of Renal Disease on Drug
Distribution
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Binding of acidic drugs (phenytoin,
sulfonamides, warfarin, furosemide) is
decreased in uremic patients.
Displaced from albumin by organic acids that
accumulate in uremia.
Higher concentration of free drug may alter
interpretation of therapeutic range
Effect of Renal Disease on Drug
Distribution
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Presence of edema and ascites may increase
volume of distribution of hydrophilic and
highly protein bound drugs
In nephrotic syndrome (with extensive loss of
plasma proteins) the binding of clofibric acid,
the active metabolite of clofibrate, decreases.
This results in an increased volume of
distribution
Effect of Renal Disease on Drug
Distribution
Drug
Volume of distribution (L/kg)
Normal
ESRD
Increased V
• Furosemide
• Gentamicin
• Phenytoin
• Trimethoprim
0.11
0.2
0.64
1.36
0.18
0.29
1.4
l.83
Decreased V
• Digoxin
• Ethambutol
7.3
3.7
4.1
1.6
Measurement and
Estimation of Creatinine
Clearance
Introduction
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Glomerular filtration rate can be determined by
administration of special test compounds such as inulin or
125I-iothalamate; this is sometimes done for patients by
nephrologists when precise determination of renal function
is needed
Glomerular filtration rate (GFR) can be estimated using the
modified Modification of Diet in Renal Disease (MDRD)
equation:
GFR (in mL/min / 1.73 m2) = 186×SCr −1.154×Age−0.203×(0.742,
if female)×(1.21, if African-American)
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For example, the estimated GFR for a 53-year-old AfricanAmerican male with a SCr = 2.7 mg/dL would be computed
as follows: GFR = 186 ⋅ (2.7 mg/dL)−1.154 ⋅ (53 y)−0.203 ⋅
1.21 = 32 mL/min / 1.73 m2
Introduction
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However, the method recommended by the Food and Drug
Administration (FDA) and others to estimate renal function
for the purposes of drug dosing is to measure or estimate
creatinine clearance (CrCl).
Creatinine is a by-product of muscle metabolism that is
primarily eliminated by glomerular filtration
Because of this property, it is used as a surrogate
measurement of glomerular filtration rate
Since creatinine is also eliminated by other routes, CrCl
does not equal GFR, so the two parameters are not
interchangeable.
Equations for body surface
area (BSA):
BSA(m )  0.007184 x (HT
2
BSA in m
Wt in kg
Ht in m
2
Reference: Dubois; Arch Internal Med 1916;17:863
0.725
x WT
0.425
)
Equation for Ideal Body Weight
(IBW):
IBW (male, kg)  50  (2.3 x Ht in inches over 5 feet)
IBW (female, kg)  45  (2.3 x Ht in inches over 5 feet)
1 feet  12 inch
1 inch  2.54 cm
Devine; Drug Intell Clin Pharm 1974;8:650
Estimation of GFR using
serum creatinine (Scr)
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Creatinine is endogenous substance derived from
muscle metabolism, small & not bound to plasma
proteins, maintains a fairly constant level, and
predominantly filtered ~85% (~15% TS) with minimal
non-renal elimination.
Proportional to muscle mass & body weight
Normal 24-hour excretion: 20-25 mg/kg IBW (males)
and 15-20mg/kg (females)
Creatinine production decreases with age:
2mg/kg/24hrs per decade
Several equations have been published to predict
GFR using creatinine clearance (Clcr)
Estimation of GFR using
Cockcroft-Gault Equation
Wt(140 - Age)
Males : Clcr(ml/mi n) =
SCr x 72
Females : Clcr = 85% of male value
Wt : kg
Age : years
SCr : mg/dl
Cockroft D.W., Gault M.H. Prediction of creatinine clearance from serum
creatinine. Nephron. 1976;16(1):31-41
Estimation of GFR using
Cockcroft-Gault Equation
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Actual body weight (BW) is used in underweight
patients (BW < IBW)
Ideal body weight (IBW) in patients of normal weight
(BW < 1.3*IBW)
Adjusted body weight (ABW) is used for overweight,
obese, and morbidly obese patients (BW >
1.3*IBW), suggest use Salazar & Corcoran equation
ABW  IBW  0.4  (BW - IBW)
Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations
on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy 2012;32:604-12.
Estimation of GFR using
Cockcroft-Gault Equation
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Elderly: The Cockcroft & Gault equation tends to over-estimate CLCR in the
elderly. Therefore, an empiric "correction" commonly employed is to round up
the serum creatinine to 1.0 mg/dL in elderly patients. However, most studies
have found this to be an inappropriate practice which under-estimates true ClCr.
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Very low serum creatinine: Use of a very low serum creatinine (0.5 mg/dL or
less) in the C&G equation leads to a falsely elevated ClCr. Therefore, many
practitioners designate 0.7 mg/dL as the minimum SCr which should be used in
the equation.
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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.
Estimation of GFR in obese patients (>130% X
IBW) using Salazar-Corcoran Equation
Males :
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137 - Age   (0.285  Wt)  (12.1 x Ht
Clcr(ml/mi n) 

2
)
2
)
(51 x Scr)
Females :
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146 - Age   (0.287  Wt)  (9.74 x Ht
Clcr(ml/mi n) 
(60 x Scr)
Ht in meters, Wt is the actual body weigh t in Kg
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
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Estimation of Clcr in Pediatrics
Infants up to 1 year of age
0.45 X Ht (cm)
Clcr (mL/min/1. 73m ) 
Scr
Children 1 to 10 years of age
0.55 X Ht (cm)
Clcr (mL/min/1. 73m ) 
Scr
Schwartz GJ et al. J Pediatr. 1984;104:849-54 and Pediatrics. 1976;58:259-63.
Patients with unstable renal
function: Jelliffe's multi step
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If serum creatinine values are not stable, but
increasing or decreasing in a patient, the
Cockcroft-Gault equation cannot be used to
estimate creatinine clearance. In this case,
an alternate method must be used which was
suggested by Jelliffe and Jelliffe
Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972
Jelliffe Multi-step method
1.
Estimate creatinine Volume of distribution
(Vcr)
Volume of distributi on (in dL)  4  BW
Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972
Jelliffe Multi-step method
2.
Estimate creatinine production
Creatinine production (mg/day) 
[29.305 - (0.203  age)]  BW  [1.037 - (0.0338  average SrCr]  Correction
where Correction  0.85 for males and 0.765 for females
Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972
Jelliffe Multi-step method
3.
Estimate creatinine clearance (ml/min)
Creatinine clearance (ml/min) 


SCr1 - SCr2 
 Volume of distributi on  
  creatinine production   100
t




1440  Average SCr
where Scr1 is the first serum creatinine and Scr2 is the
second serum creatinine both in mg/dL, and Δt is the
time that expired between the measurement of Scr1
and Scr2 in days
When SCr rises, last SCr observation is used instead of
average SCr
Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972
Jelliffe Multi-step method
4.
Estimate creatinine clearance (standardized
to BSA, ml/min/1.73m2 )
2
Clcr
(ml/min)

1.73m
2
Clcr ( ml/min/1.7 3m ) 
BSA
Jelliffe RW, Jelliffe SM. Math Biosci. 14:17-24 (June) 1972
Estimation of GFR using
Jelliffe Multi-step method
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Actual body weight (BW) is used in underweight
patients (BW < IBW)
Ideal body weight (IBW) in patients of normal
weight (BW < 1.3*IBW)
Adjusted body weight (ABW) is used for
overweight, obese, and morbidly obese patients
(BW > 1.3*IBW)
ABW  IBW  0.4  (BW - IBW)
Estimation of GFR by calculating
Clcr from 24-hour urine collection
creatinine production rate (mg/1440mi n)
Clcr(ml/mi n) 
SCr (mg/100ml)
Ucr  Uvol

SCr 1440
Where:
Ucr = urine creatinine concentration (mg/dL);
Uvol = total urine volume (ml/24 hrs);
SCr = serum creatinine (mg/dL)
Estimation of GFR by calculating
Clcr from 24-hour urine collection
2
Clcr
(ml/min)

1.73m
2
Clcr ( ml/min/1.7 3m ) 
BSA
Example 1
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A creatinine clearance is measured in a 75year-old Caucasian male patient with multiple
myeloma to monitor changes in renal
function. The serum creatinine, measured at
the midpoint of the 24 hour urine collection,
was 2.1 mg/dL. Urine creatinine
concentration was 50 mg/dL, and urine
volume was 1400 mL. Calculate this patient’s
creatinine clearance.