Clinical Evaluation of Glomerular Filtration

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Clinical Evaluation of Glomerular Filtration

• S.P. DiBartola, DVM
• D.J. Chew, DVM

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The ideal substance to measure GFR would

• 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

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Clinical Assessment of GFR

• BUN
• Serum creatinine
• Creatinine clearance (endogenous or exogenous)
• Sodium sulfanilate
• Radioisotopes

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Essential terminology

• Renal disease
• Renal failure
• Azotemia
• Uremia

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Renal disease

• Implies the presence of histologic lesions in the
  kidney but does not specify any degree of renal
  dysfunction

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Renal failure

• Implies that 75 of the total nephron population
  has become non-functional but does not
  necessarily imply underlying histologic lesions

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Azotemia

• Increased concentration of non-protein
  nitrogenous waste products (e.g. urea,
  creatinine) in the blood

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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

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Uremia

• The constellation of clinical and biochemical
  abnormalities associated with a critical loss of
  functioning nephrons
• Includes the extra-renal manifesations of renal
  failure

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Blood urea nitrogen (BUN)

• 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
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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
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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)

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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

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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)

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Abnormal BUN Non-renal factors

• Increased BUN
• 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)

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Creatinine

• 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
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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

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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

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Measurement of creatinine

• Usually measured by alkaline picrate method (used
  on Hitachi autoanalyzer)
• Measures creatinine and non-creatinine chromagens

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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

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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)

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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

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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

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Implication of azotemia

• In a steady state and when non-renal 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

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Magnitude of azotemia does NOT

• Differentiate pre-renal, renal, and post-renal
  processes
• Differentiate acute from chronic processes
• Differentiate reversible from irreversible
  processes
• Differentiate progressive from non-progressive
  processes

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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

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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

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Localization of azotemia

• Must consider
• History
• Physical examination findings
• Urine specific gravity before fluids or drugs
  that may interfere with concentrating ability
• Patients response to fluid therapy

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Localization of azotemiaExample 1

• 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

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Localization of azotemiaExample 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

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Localization of azotemiaExample 3

• 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

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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

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Clearance UxV/Px

• Where,
• Ux urine concentration of x (mg/dL)
• Px plasma concentration of x (mg/dL)
• V urine output (mL/min)

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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

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Relationship of clearance to GFR

• If X is neither reabsorbed nor secreted,
  clearance GFR
• If X is reabsorbed, clearance lt GFR
• If X is secreted, clearance gt GFR

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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

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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

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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)

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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

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Indications for creatinine clearance

• Suspicion of renal disease in a non-aoztemic
  patient with PU/PD

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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)

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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
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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

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Radioisotopes

• Glomerular filtration rate
• 125I-iothalamate
• 51Cr-ethylenediaminetetraacetic acid (EDTA)
• 99mTc-diethylenetriaminepentaacetic acid (DTPA)
• Renal plasma flow
• 131I-iodohippurate
• 3H-tetraethylammonium bromide