2. ANATOMY
Highly differentiated organ
Renal blood flow normally drains ~20% of the
cardiac output, or1000 mL/min.
Filtration is determined by
molecular size to lesser
extent by charge
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9. gfr
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Glomerular filtration rate (GFR)
is the product of the average filtration rate of each nephron
normal level for GFR is approximately 130 ml/min/1.73 m² for men and
120 ml/min/1.73 m² for women
10. gfr
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• GFR correlates well with
health and disease
• Both tubular secretion and absorption
• Endocrine and metabolic function of the kidney
11. Plasma clearance of substance x (Cx) can be
calculated as Cx = Ax/Px
AX - eliminated amount of substance x
Px – plasma level of substance x
In the steady state, substance x is maintained at
constant plasma level.
To decrease non-GFR determinants equations
use clinical and epidemiologic variables giving
more accurate estimated GFR.
Other sources of error
Measurement error - Poor
calibration
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12. gfr
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Endogenous chemicals used to estimate GFR
Solutes that are <20,000Da, not bound with plasma proteins, freely
filtered by the glomerulus
Endogenous – usually produced in a steady state
Creatinine
Urea, cystatin c
Exogeneous
Inulin
Iothalamate, iohexol, ethylenediaminetetraacetic acid, and diethylenetriaminepentaacetic acid
13. Gfr
Factors affecting GFR
Age
Gender
body size
physical activity
diet,
pharmacotherapy,
Hyperglycemia
physiologic states such as
pregnancy
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14. gfr
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Age – decline with age; the mean rate of decline is approximately 0.75 ml/min/year after 40 years of
age.
Gender – 8% higher in men than women
body size – BSA is used to counter the body size of the body (/ml min/1.73m²)
physical activity, diet, pharmacotherapy, hyperglycemia, and physiologic states such as
15. gfr
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Pregnancy - GFR increases by about 50% in the first trimester and returns to normal immediately
after delivery
Diurnal variation - and is 10% lower at midnight compared with the afternoon
Reductions in GFR could result from
Single nephron GFR decrement with-out loss of nephron number
Due to loss of nephrons
16. creatinine
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Creatinine is
Metabolite of phosphocreatine from muscle
Free not protein bound,
Freely filtered across glomerulus
Secreted by tubules
drugs that affect creatinine level
cimetidine, trimethoprim, and possibly fenofibrate
Some cephalosporins and flucytosine
Cystatin C – cellular product
17. gfr
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GFR calculation equations
Cockcroft-Gault formula
CrCl = [(140 - age) x IBW] / (Scr x 72) (x 0.85 for females)
IBW calculator =
MDRD equation
Estimated GFR (ml/min/1.73m2) = 186 x (Scr/ 88.4)-1.154 x (Age)-
0.203 x (0.742 if female) x (1.210 if black)
CKD-EPI equation
GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018
[if female] × 1.159 [if African American]
18. gfr
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Still GFR calculations don’t consider
extreme levels for creatinine generation
amputees
large or small individuals
muscle-wasting conditions
atypical pattern of meat consumption
19. DRUG DOSING AND RENAL FUNCTION
TEST
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Pharmacokinetics of many drugs is affected by acute and
chronic disease
Drug dosing calculation with MDRD equation should use ml/min
than /1.73m²
Body surface area =0.20247 x height (m)0.725 x mass (kg)0.425
The Cockcroft-Gault formula was widely used.
20. AKI and drug dosing
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Recommendations for metabolized medications in AKI include
more close monitoring than current clinical practice
– Frequent monitoring of drug pharmacodynamics
– Therapeutic drug monitoring/pharmacokinetic analysis
• Limited by availability of laboratory testing in clinically
relevant time-frame
21. AKI AND DRUG DOSING
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Duration of AKI may also be important
– Using dosing recommendations for CKD and ESRD early in AKI for drugs with a
significant nonrenal clearance component may lead to subtherapeutic levels
– Higher dosing may be needed early in course with later reduction in dose
and/or frequency as AKI persists and nonrenal clearance attenuates
22. Ckd and drug dosing
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GFR is assumed to capture all aspects of effect of kidney yet
No incorporation of other factors that may not correlate with GFR,
but are present in patients with CKD, e.g. hypoalbuminemia or drug
interactions
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)2009 creatinine equation was developed from a large database of people,including those with and without kidney disease, diabetes, and a historyof organ transplantation.8 The equation includes age, race, and sex andstandardized serum creatinine. It uses a two-slope “spline” to modelthe relationship between GFR and serum creatinine and is accurateacross the full range of GFR. It is accurate across a wide range of patientcharacteristics, including age, gender, race, body mass index (BMI),and presence or absence of diabetes or history of organ transplantation.The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that clinical laboratories use CKD-EPI creatinineequations to report eGFR in all adults whenever serum creatinine ismeasured or use other equations if shown to be superior to CKD-EPIequation in that population
The Cockcroft-Gault equation, developed in 1977, estimates Clcr fromage, gender, and body weight, in addition to serum creatinine.10 Comparison to normal values for Clcr requires computation of BSA andadjustment to 1.73 m2. The Cockcroft-Gault formula has several limitations. First, it is not precise, in particular in the GFR range above 60 ml/ min. Second, it estimates Clcr rather than GFR and thus is expected tooverestimate GFR. Third, the formula was derived by older assay methodsfor serum creatinine, which cannot be calibrated to newer assay methodsand would be expected to lead to a systematic bias in estimating Clcr.Fourth, it systematically overestimates Clcr in edematous or obesepatients. Fifth, the large age term means that all older adults will havelower levels of estimated GFR.The Modification of Diet in Renal Disease (MDRD) study equation11is similar to the CKD-EPI equation and more accurate than the CockcroftGault equation. However, it was derived from a study population withCKD, so it underestimates the measured GFR in populations with higherlevels of GFR, and numeric values cannot be reported for GFR levelsgreater than 60 ml/min/1.73 m2.12