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The kidney plays a major role in clearance of drugs and their metabolites from the body.
Renal clearance occurs through glomeruli filtration, renal tubular
secretion, and renal tubular reabsorption. Drugs may be totally or partially
cleared by the kidneys. As renal function declines, clearance of drugs
primarily renally
eliminated declines in a proportional manner. This is reflected by an
increase in drug levels and half-life, which may lead to toxicity.
Monitoring of renal function allows for appropriated modification of drug
regimens to prevent toxicity.
Creatinine clearance provides an
estimation of glomeruli filtration rate (GFR). Creatine is produced by the
liver, pancreas, and kidneys. It is a high energy substrate used by muscles.
Creatinine is the metabolic by product which is produced at constant
rate of 1.5-2% of the total pool. Creatinine production is
determined by lean muscle mass and is therefore impacted by sex and age. Creatinine
is distributed into total body water with a volume of distribution 0.6
L/kg.
Female production is approximately 85% of males. Creatinine production declines
throughout life as muscle mass declines. The rate of creatinine
production is constant for an individual over a finite time span. Creatinine is mainly filtered in the glomerulus, with a small proportion
excreted by active tubular secretion. Creatinine clearance is useful for
estimating GFR.
As renal function declines
tubular secretion account for a greater percentage of creatinine clearance.
Tubular secretion is inhibited by numerous medications including: amiloride,
cimetidine, trimethoprim, salicylate, triamterene, and spironolactone.
Cimetidine 800 mg Q12H may be used to inhibit tubular secretion to obtain a
more accurate estimation of creatinine clearance.
Medications may interfere with creatinine assays. Jaffe based assays are
interfered by acetoacetate, bilirubin, cefoxitin, cephalothin, clavulanic
acid, lactulose. Enzymatic assays are interfered by dopamine, dobutamine,
flucytosine and lidocaine.
Accuracy of calculations may be impacted
by conditions affecting muscle mass or muscle function: amputations, spinal
cord injury, liver disease, malnourishment, and obesity. Bayesian dosing
methods are not recommended in patients whose production of creatinine is
significantly lower that the model's studied population as mean
pharmacokinetic parameters will be significantly different. The predicted
levels will be much lower than actual levels and erroneous dosing
recommendation will be made.
Attention should be focused on actual levels achieved and not on the
predicted levels.
Amputations
Adjustment of ideal or lean body weight by percentage
weight lost: 5% entire upper limb, 3.3% above the elbow, 2.3% below
the elbow, 16% entire lower limb, 8% above the knee, 5.9% below
the knee amputation, and 1.5% for foot.
Liver Dysfunction
Severe liver dysfunction decreases serum creatinine likely due to low muscle
mass, decreased liver function, protein malnutrition, and proportionally
increased secretion of creatinine, especially at low GFR. Creatinine-based
equations for glomerular filtration rate estimation have been proven to be
inaccurate for cirrhotic patients. Specific equations or correction factors
for creatinine based GFR are unavailable for liver dysfunction. Elevation in
serum creatinine in cirrhosis is indicative of the presence of either an
acute kidney injury (AKI) or chronic kidney disease (CKD). If the BUN/Scr ratio is elevated and total bilirubin is
elevated the serum creatinine may be falsely low and conservative dosing and
therapeutic drug monitoring should be more aggressive. It is common to
observe patients being overdosed when healthcare providers failed to
associated these values with low creatinine production and erroneous
creatinine clearance calculations.
Rounding of Serum
Creatinine Values
Rounding up of low serum creatinine values to 0.7 mg/dl in non-spinal cord
injury patients and 0.5 mg/dl in spinal cord injury is recommended to
prevent under/over dosing, along
with serum level monitoring as applicable.
Serum
Creatinine (mg/ml) = Rate of Creatinine Production (mg/min) / Clearance of
Creatinine (ml/min)
Clearance of
Creatinine (ml/min) = Rate of Creatinine Production (mg/min) / Serum
Creatinine (mg/ml)
Rate of Production used in Cockcroft-Gault Equation
Males
mg/hr =(28 -(0.2*Age
years))*Weight
kg/24
Female
mg/hr= 0.85*
above
Equations for Calculating Creatinine Clearance
and Drug Dosing
Adults with stable renal function
Cockcroft-Gault
Males Crcl
ml/min
= (140-age
years) Weight
kg / (72 * Scr
mg/dl )
Females Crcl
ml/min = 0.85 x above
Weight is ideal body weight or actual weight (ABW) if lower than ideal for
non-obese.
Weight = IBW + 0.4
* (ABW
kg - IBW
kg) for obese
Ideal Body Weight
(IBW)
Males
kg = 50 + 2.,3*(Height
Inches - 60)
Females
kg = 45.5 +2.3* (Height
Inches - 60)
Lean Body Weight
Males kg = (9270*ABW) / [6690 + (216
x BMI)]
Females kg = (9270*ABW) / [8780 + (244*BMI)]
Calculating Creatinine Clearance Calculations With Changing Renal
Function
Assumptions of non-steady state equations:
All of the change in renal function has occurred
at or before the time of the oldest creatinine (creatinine1). If change is
still occurring the calculated value will under estimated the true change. The change
in creatinine is due to renal function changes and is not due to tissue
destruction or hydration changes.
MSS Chow Equation For Iterative Calculation of
Creatinine Clearance
This is the most accurate method for calculation of
creatinine clearance after changes in renal function and is incorporated in
most dosing tools on this site.
Creatinine
Concentrations, Comparison of Multiple Methods. MSS Chow Drug Intelligence
and Clinical Pharmacy 1985;19:385-90)
Serum Creatinine2
mg/L= Serum Creatinine1
mg/L* e
(-KT)
+ Rate of Production (1-e
(-KT))
K is found through an
iterative data fitting method or my using the Solver add-in in Excel
Crcl
L/hr=
K
1/hr*Vd
LCrcl
ml/min = Crcl
L/hr
*1000 ml/L/60minutes/hr
Rate In of Creatinine from Cockcroft-Gault Equation
Males
mg/hr =(28 -(0.2*Age
years))*Weight
kg/24
Female
mg/hr= 0.85*
above
Weight is LBW or Actual Weight is less, or adjusted weight in obese
T
hours is the time between serum the serum creatinines.
Vd
l/kg of creatinine
is 0.6
l/kgK
1/hr is the calculated elimination rate constant for creatinine
calculated.
This equation
accounts for the elimination of creatinine already present and the fraction
of steady state achieved during the time between the creatinines.
ASHP
Clinical Pharmacokinetics
Clrcl
rml/min males = ([[293-2.03*Age
years]*[1.035-0.01685(Scr1
+ Scr2)]] + [49*(Scr1-Scr2)/Time Change] ) /(Scr1+Scr2)
Crck
rml/min
females = 0.86 * above
Mass Balance Equation From Winter's
Basic Pharmacokinetics
Crcl
ml/min= [[ (Production of Creatinine
mg/day) -
[(Scr2-Scr1)*0.6*Weight) / Time
day)*10dl/L ] ] / (Scr2*10dl/L) ] *
(1000
ml/L/1440 min/day)