Transcript PowerPoint Presentation - Clinical Evaluation of

Clinical Evaluation of
Glomerular Filtration
S.P. DiBartola, DVM
D.J. Chew, DVM
The ideal substance to measure GFR
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Be freely filtered at the glomeruli
Not be bound to plasma proteins
Not be metabolized
Be non-toxic
Be excreted only by the kidneys
Be neither reabsorbed nor secreted by the
renal tubules
• Be stable in blood and urine
• Be easily measured
Clinical Assessment of GFR
• BUN
• Serum creatinine
• Creatinine clearance
(endogenous or exogenous)
• Sodium sulfanilate
• Radioisotopes
Essential terminology
• Renal disease
• Renal failure
• Azotemia
• Uremia
Renal disease
• Implies the presence of histologic
lesions in the kidney but does not
specify any degree of renal
dysfunction
Renal failure
• Implies that 75% of the total
nephron population has become
non-functional but does not
necessarily imply underlying
histologic lesions
Azotemia
• Increased concentration of nonprotein nitrogenous waste
products (e.g. urea, creatinine) in
the blood
Azotemia
• Pre-renal: due to reduced renal
perfusion
• Renal: due to renal parenchymal
disease
• Post-renal: due to impaired
elimination of urine from the body
Uremia
• The constellation of clinical and
biochemical abnormalities
associated with a critical loss of
functioning nephrons
• Includes the extra-renal
manifesations of renal failure
Blood urea nitrogen (BUN)
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Dogs: 8-25 mg/dL
Cats: 15-35 mg/dL
Horses: 10-27 mg/dL
Cattle: 5-23 mg/dL
Normal values may vary among laboratories
Production of urea
• Synthesized in liver
using NH3 derived
from amino acids of
endogenous (body) or
exogenous (dietary)
proteins
• Not produced at a
constant rate
(affected by protein
intake)
NH4+ + CO2 + 3ATP + 2H2O + aspartate  urea + 2ADP + 2Pi +
AMP + PPi + fumarate + 2H+
Distribution and excretion of urea
• Freely permeable and distributed
throughout total body water
• Renal excretion most important
• Filtered by glomeruli
• Passively reabsorbed in renal tubules
depending on tubular flow rate
• Not secreted by renal tubules
• Not excreted at a constant rate (high
protein meal transiently increases GFR)
Measurement of urea
• Technically easy and reproducible
• Measured by diacetylmonoxamine or
urease methodology
• Urease methodology most specific
and accurate (used on Hitachi
autoanalyzer)
• Dipstrip (e.g. Azostix) methods not
very accurate
Abnormal BUN concentration
• Non-renal factors
• Renal factors
• Pre-renal (e.g. dehydration, heart failure,
shock)
• Renal (e.g. parenchymal renal disease)
• Post-renal (e.g. urethral obstruction,
ruptured bladder)
Abnormal BUN: Non-renal factors
• Increased BUN
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High protein meal
Hemorrhage into gastrointestinal tract
Increased catabolism
Drugs (glucocorticoids, azathioprine, tetracycline)
• Decreased BUN
• Low protein diet
• Severe liver disease or portosystemic shunt
• Drugs (anabolic steroids)
Creatinine
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Dogs: 0.3-1.2 mg/dL
Cats: 0.8-1.8 mg/dL
Horses: 1.0-1.8 mg/dL
Cattle: 0.6-1.5 mg/dL
Normal values may vary among laboratories
Production of creatinine
• Non-enzymatic
breakdown product of
phosphocreatine in
muscle
• Produced at a
relatively constant rate
based on age, gender,
and muscle mass
• Not affected by diet
Distribution and excretion of creatinine
• Freely permeable and distributed
throughout total body water
• Renal excretion most important
• Filtered by glomeruli
• Not reabsorbed by renal tubules
• Not secreted by renal tubules
• Excreted at a relatively constant rate
Measurement of creatinine
• Usually measured by alkaline
picrate method (used on Hitachi
autoanalyzer)
• Measures creatinine and noncreatinine chromagens
Measurement of creatinine:
Non-creatinine chromagens
• May constitute up to 50% of measured
“creatinine” at normal serum creatinine
concentrations (but progressively less
as renal function declines)
• Do not appear in urine (affects
clearance calculations)
• Special techniques to circumvent them
are not in common use by clinical
laboratories
Abnormal serum creatinine
concentration
• Non-renal factors (usually transient)
• Renal factors
• Pre-renal (e.g. dehydration, heart
failure, shock)
• Renal (e.g. parenchymal renal disease)
• Post-renal (e.g. urethral obstruction,
ruptured bladder)
Abnormal serum creatinine
concentration: Non-renal factors
• Increased creatinine (usually
transient)
• Massive muscle necrosis
• Prolonged strenuous exercise
• Decreased creatinine
• Severe loss of muscle mass
• Small body size
• Young age
Relationship between BUN or
creatinine and % functional nephrons
is a “rectangular hyperbola”
• Large changes in GFR
“early” in renal disease
cause small changes in
BUN or creatinine
• Small changes in GFR
late in renal disesae
cause big changes in
BUN or serum creatinine
Implication of azotemia
• In a “steady state” and when nonrenal factors have been
eliminated from consideration, an
increase of BUN or creatinine
above normal implies that at least
75% of the nephrons are not
functioning
Magnitude of azotemia does
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• Differentiate pre-renal, renal, and postrenal processes
• Differentiate acute from chronic
processes
• Differentiate reversible from irreversible
processes
• Differentiate progressive from nonprogressive processes
BUN vs serum creatinine
• Both are relatively insensitive
indicators of renal function (one is
not more sensitive than the other)
• Serum creatinine is affected by fewer
non-renal variables
• Creatinine is not affected by passive
renal tubular reabsorption
BUN/creatinine ratio
• May be increased in pre-renal
azotemia (e.g. dehydration) due to
increased tubular reabsorption of
urea at slower tubular flow rates
• May be increased in post-renal
azotemia caused by ruptured bladder
due to easier reabsorption of urea
across peritoneal membranes
Localization of azotemia
• Must consider:
• History
• Physical examination findings
• Urine specific gravity before fluids
or drugs that may interfere with
concentrating ability
• Patient’s response to fluid therapy
Localization of azotemia
Example 1
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Hx: Persistent vomiting
PE: 10% dehydrated
Lab: BUN 70 mg/dL; USG 1.054
Response to fluids: BUN 20 mg/dL
Conclusion: Pre-renal azotemia
Localization of azotemia
Example 2
• Hx: Weight loss, lethargy, anorexia,
vomiting
• PE: 10% dehydrated
• Lab: BUN 175 mg/dL; USG 1.013
• Response to fluids: BUN 75 mg/dL
• Conclusion: Pre-renal and renal azotemia
Localization of azotemia
Example 3
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Hx: Lethargy, vomiting
PE: 10% dehydrated
Lab: BUN 70 mg/dL; USG 1.013
Response to fluids: BUN 20 mg/dL
Conclusion: Pre-renal azotemia,
underlying renal disease
Concept of clearance
• Volume of plasma that would have to be
filtered by the glomeruli in one minute
to account for the amount of that
substance appearing in the urine each
minute under steady state conditions
• Volume of plasma that contains the
amount of the substance excreted in
the urine in one minute under steady
state conditions
Clearance = UxV/Px
• Where,
• Ux = urine concentration of x
(mg/dL)
• Px = plasma concentration of x
(mg/dL)
• V = urine output (mL/min)
Relationship of clearance to GFR
• In a steady state, for a substance handled
only be the kidneys that is neither
reabsorbed nor secreted:
• Amount filtered = amount excreted
• GFR  Px = Ux  V
• GFR = UxV/Px
• Thus, the clearance of a substance that is
neither reabsorbed nor secreted is equal
to GFR
Relationship of clearance to GFR
• If X is neither reabsorbed nor
secreted, clearance = GFR
• If X is reabsorbed, clearance < GFR
• If X is secreted, clearance > GFR
Inulin clearance
• Inulin is a polymer of fructose that
meets all of the criteria for the ideal
substance to measure GFR
• Inulin clearance is the “gold
standard” for GFR determination
• Inulin must be continuously infused
into the animal to achieve a steady
state concentration in plasma
Creatinine clearance
• Creatinine is produced endogenously at a
constant rate
• It is not metabolized
• It is excreted by the kidneys by glomerular
filtration
• It is neither reabsorbed nor secreted by the
renal tubules
• Creatinine clearance can be used to
estimate GFR
Endogenous creatinine
clearance
• Requirements:
• Accurately timed collection of urine
• Body weight
• Serum and urine creatinine concentrations
• Normal = 2 to 5 ml/min/kg
• Underestimates GFR (compared to inulin
clearance) due to non-creatinine
chromagens in blood (Px increased)
Exogenous creatinine
clearance
• Serum creatinine increased 10-fold by
administration of creatinine
• Minimizes effect of non-creatinine
chromagens
• More closely approximates inulin
clearance
• Technically more difficult than
endogenous creatinine clearance
Indications for creatinine
clearance
• Suspicion of renal
disease in a nonaoztemic patient
with PU/PD
Sodium sulfanilate
• Excreted solely by glomerular
filtration
• Plasma half-life is an indicator of
GFR
• Administered IV and heparinized
blood samples collected at 30, 60 and
90 min
• Normal values: 30-80 min (depending
on species)
Sodium sulfanilate
• Advantage: Urine samples not
required
• Disadvantage: No numerical
value for GFR is obtained
Seldom used in clinical evaluation of renal function in
domestic animals
Radioisotopes
• Used to determine glomerular filtration,
renal plasma flow, and filtration fraction
in domestic animals
• Advantages
• Do not require collection of urine
• Not time consuming
• Disadvantages
• Use of radioactivity
• Require special equipment and expertise
Radioisotopes
• Glomerular filtration rate
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125I-iothalamate
51Cr-ethylenediaminetetraacetic
acid
(EDTA)
• 99mTc-diethylenetriaminepentaacetic
acid (DTPA)
• Renal plasma flow
• 131I-iodohippurate
• 3H-tetraethylammonium bromide