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RADIONUCLIDES METHODS IN VITROclearance measurement methodsRADIONUCLIDES METHODS IN VITROclearance measurement methods
Emmanuel DURANDEmmanuel DURAND
ISCORN, Mikulov, 2010Tuesday May 11th 1030-1130ISCORN, Mikulov, 2010Tuesday May 11th 1030-1130
Question 1
What is the best index for renal function?(one choice only)
Should we normalise GFR to body size?(one choice only)
A – no, neverB – yes, always, to body surface areaC – yes, most of the time, to body surface areaD – yes, always, to body weightE – yes, most of the time, to body weight
Question 3
Should we normalise GFR to body size?(one choice only)
A – no, neverB – yes, always, to body surface areaC – yes, most of the time, to body surface areaD – yes, always, to body weightE – yes, most of the time, to body weight
Question 4
What could best characterise urine clearance measurements, as compared to plasma clearance measurements?(one choice only)
A – they are more precise and more accurateB – they are less precise but more accurateC – they are more precise but less accurateD – they are less precise and less accurateE – they are more precise and as accurate
Question 4
What could best characterise urine clearance measurements, as compared to plasma clearance measurements?(one choice only)
A – they are more precise and more accurateB – they are less precise but more accurateC – they are more precise but less accurateD – they are less precise and less accurateE – they are more precise and as accurate
Question 5
In which circumstance(s) should you perform a urinary clearance measurement instead of a plasma clearance measurement?(potentially several answers)
A – in childrenB – in patients with œdema C – in patients with hyperfiltrationD – in patients with very low renal functionE – in patients with asymetrical renal function
Question 5
In which circumstance(s) should you perform a urinary clearance measurement instead of a plasma clearance measurement?(potentially several answers)
A – in childrenB – in patients with œdema C – in patients with hyperfiltrationD – in patients with very low renal functionE – in patients with asymetrical renal function
Question 6
What is the general formula for clearance?P: plasma concentration – U: urinary concentrationBW : body weight – V : urine flow – CO : cardiac output(one choice only)
A – P × U / VB – U × V / PC – U × V / BWD – (C × O / V ) × (P / U)E – P × V × U
Question 6
What is the general formula for clearance?P: plasma concentration – U: urinary concentrationBW : body weight – V : urine flow – CO : cardiac output(one choice only)
A – P × U / VB – U × V / PC – U × V / BWD – (C × O / V ) × (P / U)E – P × V × U
Question 7
How is the plasma clearance determined?(one choice only)
A – the urinary concentration divided by the plasma concentrationB – the area under the plasma time-concentration curve divided by the injected activityC – the area under the plasma time-concentration curve divided by the plasma concentration at time 0D – the injected activity divided by the area under the plasma time-concentration curveE – the injected activity divided by the area under the plasma time-concentration curve
Question 7
How is the plasma clearance determined?(one choice only)
A – the urinary concentration divided by the plasma concentrationB – the area under the plasma time-concentration curve divided by the injected activityC – the area under the plasma time-concentration curve divided by the plasma concentration at time 0D – the injected activity divided by the area under the plasma time-concentration curveE – the injected activity divided by the area under the plasma time-concentration curve
Question 8
When using two plasma samples for plasma clearance technique:(potentially several answers)
A – two exponentials must be determinedB – one exponential only can be determinedC – a correction formula must be used, the recommended one being published by Brochner and MortensenD – a correction formula must be used, the recommended one being published by Christensen and GrothE – there is no need for correction
Question 8
When using two plasma samples for plasma clearance technique:(potentially several answers)
A – two exponentials must be determinedB – one exponential only can be determinedC – a correction formula must be used, the recommended one being published by Brochner and MortensenD – a correction formula must be used, the recommended one being published by Christensen and GrothE – there is no need for correction
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
• can a patient withstand nephrectomy (either for himself or as a kidney donor)• can a patient withstand nephrotoxic drugs (anti-tumoural chemotherapy)?• adapt drug dosage to renal function • detect mild renal insufficiency• renal function follow-up• prepare dialysis• can a patient stop dialysis?• how does a patient behaves under a drug (i.e. ACE inhibitors)• concept of glomerular functional reserve• determine hyperfiltration in diabetics
• can a patient withstand nephrectomy (either for himself or as a kidney donor)• can a patient withstand nephrotoxic drugs (anti-tumoural chemotherapy)?• adapt drug dosage to renal function • detect mild renal insufficiency• renal function follow-up• prepare dialysis• can a patient stop dialysis?• how does a patient behaves under a drug (i.e. ACE inhibitors)• concept of glomerular functional reserve• determine hyperfiltration in diabetics
CLINICAL INDICATIONSCLINICAL INDICATIONS
concept of glomerular functional reserveconcept of glomerular functional reserve
After infusion of:• either Dopamin 2 µg/kg/min• or some amino-acids (Hyperamin 50 mL/hr)• or bothglomerular filtration rate increases by about 15%
After infusion of:• either Dopamin 2 µg/kg/min• or some amino-acids (Hyperamin 50 mL/hr)• or bothglomerular filtration rate increases by about 15%
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
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CONCEPT: functionCONCEPT: function
best parameter to assess renal function =best parameter to assess renal function =
Levey AS. Use of glomerular filtration rate measurements to assess the progression of renal diseaseSemin Nephrol 1989;9(4):370-9
Levey AS. Use of glomerular filtration rate measurements to assess the progression of renal diseaseSemin Nephrol 1989;9(4):370-9
• keep homeostasis (water, ions, )• excretion of toxic substances• metabolism (1-hydroxylation of vitamin D)• hormonal: erythropoietin, renin
• keep homeostasis (water, ions, )• excretion of toxic substances• metabolism (1-hydroxylation of vitamin D)• hormonal: erythropoietin, renin
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
clearance is the imaginary plasma flow cleared from substancei.e. kidney ability to ‘clean’ plasma from substance
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CONCEPT: clearanceCONCEPT: clearance
Clearance : Clearance : U VC E FP×
= = ×U VC E FP×
= = ×
definition :imaginary plasma flow (volume per unit time)completely cleared from substance
definition :imaginary plasma flow (volume per unit time)completely cleared from substance
for a given organ:ability to take the subtance including the input function (perfusion)
= plasma flow × extraction
for a given organ:ability to take the subtance including the input function (perfusion)
= plasma flow × extraction
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CONCEPT: clearanceCONCEPT: clearance
Clearance reflects renal functionas if the role of the kidney were to remove a substance from the blood(which is a shortcut)
Clearance reflects renal functionas if the role of the kidney were to remove a substance from the blood(which is a shortcut)
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
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CONCEPT: glomerularCONCEPT: glomerular
A glomerular traceris a small molecule, freely filtered, not linked to proteinsnot secreted nor reabsorbed
A glomerular traceris a small molecule, freely filtered, not linked to proteinsnot secreted nor reabsorbed
its concentration in the plasma isits concentration in the plasma is PP
its concentration in the glomerular filtrate (primary urine) is alsoits concentration in the glomerular filtrate (primary urine) is also PP
its flow in the glomerular filtrate isits flow in the glomerular filtrate is GFRP×GFRP×
GFR GFRPCP×
= =GFR GFRPCP×
= =its clerance is thereforeits clerance is therefore
as it is not secreted nor reabsorbed, its flow in the final urine is also
as it is not secreted nor reabsorbed, its flow in the final urine is also GFRUV P= ×GFRUV P= ×
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CONCEPT: glomerularCONCEPT: glomerular
A glomerular traceris a small molecule, freely filtered, not linked to proteinsnot secreted nor reabsorbed
A glomerular traceris a small molecule, freely filtered, not linked to proteinsnot secreted nor reabsorbed
Its clearance is the glomerular filtration rateIts clearance is the glomerular filtration rate
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
« Gold Standard »: Inulin (cold, exogenous)« Gold Standard »: Inulin (cold, exogenous)
Exogenous cold tracer (former gold standard) = inulinExogenous cold tracer (former gold standard) = inulinfructose polymer (polyfructosan)extracted from Jerusalem artichokeconsidered as a gold standardthough, also cleared by other organsassays are not straightforwardno more widely available for in vivo human use
fructose polymer (polyfructosan)extracted from Jerusalem artichokeconsidered as a gold standardthough, also cleared by other organsassays are not straightforwardno more widely available for in vivo human use
Endogenous tracer used in clinical routine : creatinineEndogenous tracer used in clinical routine : creatinineendogeneous: no injection is neededproduced by protein catabolismproduction is not constant (muscles / food intake)not only filtered but secretedassays are not straightforward (many interferences)assay results strongly depends on technique
endogeneous: no injection is neededproduced by protein catabolismproduction is not constant (muscles / food intake)not only filtered but secretedassays are not straightforward (many interferences)assay results strongly depends on technique
• plasma creatinine with formulaeCockroft and Gault, MDRD, Schwartz, Counahan-Barratt…
• plasma creatinine with formulaeCockroft and Gault, MDRD, Schwartz, Counahan-Barratt…
U VCP×
=U VCP×
=
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Using only the MDRD formula is still debatedconsidered to be reliable within a ± 30% confidence inteval!unsuitable to children, elder people, obese, very thin, patients with advanced renal of hepatic insufficiency…
Using only the MDRD formula is still debatedconsidered to be reliable within a ± 30% confidence inteval!unsuitable to children, elder people, obese, very thin, patients with advanced renal of hepatic insufficiency…
Coresh. J Am Soc Nephrol 2002;13(11):2811-2.Agarwal R. Am J Kidney Dis 2005;45(3):610-3.Rule. Am J Kidney Dis 2004;43(1):112-9.
Coresh. J Am Soc Nephrol 2002;13(11):2811-2.Agarwal R. Am J Kidney Dis 2005;45(3):610-3.Rule. Am J Kidney Dis 2004;43(1):112-9.
radiotracers still have a roleradiotracers still have a role
51Cr-EDTA (Ethylene-Diamine-TetrAcetate)51Cr-EDTA (Ethylene-Diamine-TetrAcetate)51Cr : T1/2 = 27,7 j CE + γ 320 keV (10%)no imaging, only clearancealready labeled in 1 mCi vialsexcellent in vitro and in vivo stabilitypresent gold standard(small extra-renal clearance ~ 4 mL/min.)
51Cr : T1/2 = 27,7 j CE + γ 320 keV (10%)no imaging, only clearancealready labeled in 1 mCi vialsexcellent in vitro and in vivo stabilitypresent gold standard(small extra-renal clearance ~ 4 mL/min.)
99mTc-DTPA (Diethylene-Tetramine-PentAcetate)99mTc-DTPA (Diethylene-Tetramine-PentAcetate)imaging and/or clearancescold kitgood in vitro and in vivo stabilityprotein binding should be checked for (depends on brand used)labeling yield (free Tc and reduced-hydrolysed Tc)
imaging and/or clearancescold kitgood in vitro and in vivo stabilityprotein binding should be checked for (depends on brand used)labeling yield (free Tc and reduced-hydrolysed Tc)
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Among Glomerular tracers:• EDTA-51Cr is a tracer of choice (unavailable in the USA)• DTPA-99mTc is good provided protein binding is checked
(strong variations among preparations)
iothalamate is only a second choice (USA)it is also secreted
Among Glomerular tracers:• EDTA-51Cr is a tracer of choice (unavailable in the USA)• DTPA-99mTc is good provided protein binding is checked
(strong variations among preparations)
iothalamate is only a second choice (USA)it is also secreted
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
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METHODS: types of clearancesMETHODS: types of clearances
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
ED - ISCORN'2010 - Mikulov
METHODS: urinaryMETHODS: urinary
timetime
single shotsingle shot plasma clearanceplasma clearance
In fact, any scheme of injection suits (IV, infusion, even SC)hydrate well (urine flow should exceed 3 mL/min)plasma samplingurine collectionindividual GFR determination for each collection periodvalue averaging (discard when flow < 1 mL/min)
In fact, any scheme of injection suits (IV, infusion, even SC)hydrate well (urine flow should exceed 3 mL/min)plasma samplingurine collectionindividual GFR determination for each collection periodvalue averaging (discard when flow < 1 mL/min)
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
• roughly estimate GFR from creatinine• inject a loading dose (22 kBq/kg BW)• then infuse with constant flow (7 kBq/[ml/min GFR])• plasma sampling between 1½ et 4 h after the infusion start• no need for accurate timing• urine collection is required if GFR<15 mL/min or ascites or oedema• the infusion solution is calibrated by “infusing” tubes
• roughly estimate GFR from creatinine• inject a loading dose (22 kBq/kg BW)• then infuse with constant flow (7 kBq/[ml/min GFR])• plasma sampling between 1½ et 4 h after the infusion start• no need for accurate timing• urine collection is required if GFR<15 mL/min or ascites or oedema• the infusion solution is calibrated by “infusing” tubes
• nearly no possible error (very robust)• dynamic (baseline+test condition are feasible)
(glomerular reserve/ACE inhibitors…)• precise• can be used with a urinary clearance
• nearly no possible error (very robust)• dynamic (baseline+test condition are feasible)
(glomerular reserve/ACE inhibitors…)• precise• can be used with a urinary clearance
• requires a several hour infusion• impurities may accumulate in the plasma• cumbersome ?
• requires a several hour infusion• impurities may accumulate in the plasma• cumbersome ?
• no precise timing needed• standard calibration is very easy and robust• trained nurses find it no more time-consuming than single-shot clearance
• no precise timing needed• standard calibration is very easy and robust• trained nurses find it no more time-consuming than single-shot clearance
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Single injection plasma clearanceSingle injection plasma clearance
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
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Express injected activity in the same way as the activity per unit of volume, usually detected activity:i.e. counts per minute (cpm) but might be Bq, g, mol…
Express injected activity in the same way as the activity per unit of volume, usually detected activity:i.e. counts per minute (cpm) but might be Bq, g, mol…
In practice, for the two-exponential technique :• sample from 5-10 min. post injection• up to 3-24 h according to expected renal function• 8 samples is good• cumbersome � alleviate burden is desirable
… simplified techniques!
Single injection plasma clearanceSingle injection plasma clearance
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
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The measured P(t) is lower than the true P(t)Denominator is underestimatedClearance is overestimatedCalculated clearance should be reducedThe higher the renal function, the higher the error
The measured P(t) is lower than the true P(t)Denominator is underestimatedClearance is overestimatedCalculated clearance should be reducedThe higher the renal function, the higher the error
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METHODS: bolus injection plasma clearance METHODS: bolus injection plasma clearance Calculated clearance should be corrected (reduced):Calculated clearance should be corrected (reduced):
• multiply by a number < 1 (Chantler):0.93 for adults / 0.87 for children
• use a 2nd degree formula: ax²+bx (Brøchner-Mortensen)• use a more physiologiocal formula (recommended)
Flemingimproved by Jødal and Brøchner-Mortensen
• multiply by a number < 1 (Chantler):0.93 for adults / 0.87 for children
• use a 2nd degree formula: ax²+bx (Brøchner-Mortensen)• use a more physiologiocal formula (recommended)
Scand J Clin Lab Invest 69:305 – Nucl Med Comm 28:315 Scand J Clin Lab Invest 69:305 – Nucl Med Comm 28:315 Fleming: same assuming BSA is 1.33 m²(calculation after normalisation to BSA)Fleming: same assuming BSA is 1.33 m²(calculation after normalisation to BSA)
here the clearance values are not normalised to BSAhere the clearance values are not normalised to BSA
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In practice, for slope-intercept technique (mono-exponential):• sample 2-4 samples starting no earlier than 60-90 min• fit the plasma activity decay to a single exponential• calculate the uncorrected clearance value
• compensate for single exponential (preferably with Jødal formula)
In practice, for slope-intercept technique (mono-exponential):• sample 2-4 samples starting no earlier than 60-90 min• fit the plasma activity decay to a single exponential• calculate the uncorrected clearance value
• compensate for single exponential (preferably with Jødal formula)
0
q qC A BP α β∞= =
+∫0
q qC A BP α β∞= =
+∫0
q qC BPβ
∞= =
∫0
q qC BPβ
∞= =
∫0
q qC BP β∞= =
∫0
q qC BP β∞= =
∫
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With slope-intercept technique, at least two-samples are required.Can it be simplified further?In principle, no! Two unknowns: ECV and GFR so two samples are needed.
However, if one makes an assumption about ECV, GFR can then be inferred with only one sample:this is the principle of single-sample techniques.
With slope-intercept technique, at least two-samples are required.Can it be simplified further?In principle, no! Two unknowns: ECV and GFR so two samples are needed.
However, if one makes an assumption about ECV, GFR can then be inferred with only one sample:this is the principle of single-sample techniques.
Single injection plasma clearanceSingle injection plasma clearance
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
general principlefull sampling (two-exponential)slope-intercept (single-exponential)single pointslope-only
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Sampling at time t.Plasma concentration of tracer is P(t).Nearly all these single sample-technique use the following intermediate parameter: apparent dilution volume:
The higher the plasma concentration,the smaller the volumethe smaller the clearance.
Sampling at time t.Plasma concentration of tracer is P(t).Nearly all these single sample-technique use the following intermediate parameter: apparent dilution volume:
The higher the plasma concentration,the smaller the volumethe smaller the clearance.
( ) ( )DqV t P t=( ) ( )DqV t P t=
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Adults Fisher and Veall 1975Morgan 1977Constable 1979Jacobsson 1983Russel 1985Christensen and Groth 1986d° simplified by Watson 1992
Adults Fisher and Veall 1975Morgan 1977Constable 1979Jacobsson 1983Russel 1985Christensen and Groth 1986d° simplified by Watson 1992
Children Groth 1984Tauxe 1987Ham and Piepsz 1991
Children Groth 1984Tauxe 1987Ham and Piepsz 1991
General Waller 1987 Russell 1985Fleming 2005
General Waller 1987 Russell 1985Fleming 2005
Many formulæ were published (most were empirical):Many formulæ were published (most were empirical):
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METHODS: bolus injection plasma clearance METHODS: bolus injection plasma clearance If we assume a single-exponential decay: If we assume a single-exponential decay: ( ) tP t B e β−= ⋅( ) tP t B e β−= ⋅
( ) ( )00Dq qECV V P B= = =( ) ( )00Dq qECV V P B= = =
( )0P B=( )0P B=
( ) ( )D t ttqB
ECV
q q q ECVV t P t e eeβ ββ− −
−
= = = =⋅
⋅
( ) ( )D t ttqB
ECV
q q q ECVV t P t e eeβ ββ− −
−
= = = =⋅
⋅
qB ECV=qB ECV=
( )lnD
ECVtV t
β− = ( )lnD
ECVtV t
β− = ( )lnD
ECVV tt
β−
=( )lnD
ECVV tt
β−
=( )t
D
ECVeV t
β−= ( )
t
D
ECVeV t
β−=
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METHODS: bolus injection plasma clearance METHODS: bolus injection plasma clearance If we assume a single-exponential decay: If we assume a single-exponential decay: ( ) tP t B e β−= ⋅( ) tP t B e β−= ⋅
( ) ( )00Dq qECV V P B= = =( ) ( )00Dq qECV V P B= = =
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METHODS: bolus injection plasma clearance METHODS: bolus injection plasma clearance Assuming ECV, Christensen and Groth devised a technique,which was simplified by Watson to get the same resultThe technique reduces in solving a 2nd degree equation*:
Assuming ECV, Christensen and Groth devised a technique,which was simplified by Watson to get the same resultThe technique reduces in solving a 2nd degree equation*:
• recommended by the international consensus (Blaufox, Santa Fe, 1996)•• recommended by the international consensus (Blaufox, Santa Fe, recommended by the international consensus (Blaufox, Santa Fe, 1996)1996)
Watson – Eur J Nucl Med 1992; 19: 827Watson Watson –– Eur J Nucl Med 1992; 19: 827Eur J Nucl Med 1992; 19: 827
Gamma-camera techniques (e.g. Gates, absolute DMSA,…):good for relative measurementsnot recommended for absolute measurements (Blaufox et al - J Nucl Med 1996; 37: 1883-1890, consensus)+ many experimental studies
no more precise than creatinine-based techniques
Gamma-camera techniques (e.g. Gates, absolute DMSA,…):good for relative measurementsnot recommended for absolute measurements (Blaufox et al - J Nucl Med 1996; 37: 1883-1890, consensus)+ many experimental studies
no more precise than creatinine-based techniques
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
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CHOICE OF METHODCHOICE OF METHOD
timetime
single shotsingle shot
timetime
continuous infusioncontinuous infusion
plasma clearanceplasma clearance
urinary clearance(renal clearance)
urinary clearance(renal clearance)
external countingexternal counting
• EDTA or DTPA?• plasma or urinary• single-shot or infusion• how many samples?• when sampling?
• EDTA or DTPA?• plasma or urinary• single-shot or infusion• how many samples?• when sampling?
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CHOICE OF METHODCHOICE OF METHODFirst of all, collect information:• indication• age• body mass• height• gender• plasma creatinine • presence of œdema/ascitis/3rd compartment• (urea)• (Black?)• (albumin)
and estimate GFR from creatinine(MDRD in adults / Schwartz in children)
ensure steady-state conditions
First of all, collect information:• indication• age• body mass• height• gender• plasma creatinine • presence of œdema/ascitis/3rd compartment• (urea)• (Black?)• (albumin)
and estimate GFR from creatinine(MDRD in adults / Schwartz in children)
ensure steady-state conditions
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CHOICE OF METHODCHOICE OF METHOD
EDTA or DTPA?both are goodDTPA can also be used for scanningEDTA is a very stable tracerDTPA should be checked for protein binding
EDTA or DTPA?both are goodDTPA can also be used for scanningEDTA is a very stable tracerDTPA should be checked for protein binding
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CHOICE OF METHODCHOICE OF METHOD
plasma or urinary?Plasma is more preciseBut urinary is more accurate and mandatory if any of:
• expected GFR < 25 mL/min/1.73 m²• ascites• œdema• third compartment
plasma or urinary?Plasma is more preciseBut urinary is more accurate and mandatory if any of:
• expected GFR < 25 mL/min/1.73 m²• ascites• œdema• third compartment
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CHOICE OF METHODCHOICE OF METHOD
single-shot or infusion?Single-shot is the most widely usedBut continuous infusion is needed for:
• assessment of glomerular functional reserve• assessment of GFR variations over various conditions
(ACE inhibitors…)Continuous infusion is very robust (kidney donors)
single-shot or infusion?Single-shot is the most widely usedBut continuous infusion is needed for:
• assessment of glomerular functional reserve• assessment of GFR variations over various conditions
(ACE inhibitors…)Continuous infusion is very robust (kidney donors)
ED - ISCORN'2010 - Mikulov
CHOICE OF METHODCHOICE OF METHOD
When single-shot is chosen1 sample is precise but it is not robust
(international consensus: Christensen & Groth / Watson)
2+ samples is more robust(British consensus: single-exponential + Brochner-Mortensen)2 samples make it possible to check VEC3 samples show if 3 points are not aligned4+ samples make it possible to exclude an aberrant pointadding samples does not increase precision much
When single-shot is chosen1 sample is precise but it is not robust
(international consensus: Christensen & Groth / Watson)
2+ samples is more robust(British consensus: single-exponential + Brochner-Mortensen)2 samples make it possible to check VEC3 samples show if 3 points are not aligned4+ samples make it possible to exclude an aberrant pointadding samples does not increase precision much
ED - ISCORN'2010 - Mikulov
CHOICE OF METHODCHOICE OF METHOD
When to sample?For single exponential: from 90 minutes post injectionFor last sampleIf expected GFR > 90 mL/min/1.73 m² up to 3 hr
> 60 mL/min/1.73 m² up to 4 hr> 40 mL/min/1.73 m² up to 5 hr< 40 mL/min/1.73 m² up to 24 hr
When to sample?For single exponential: from 90 minutes post injectionFor last sampleIf expected GFR > 90 mL/min/1.73 m² up to 3 hr
> 60 mL/min/1.73 m² up to 4 hr> 40 mL/min/1.73 m² up to 5 hr< 40 mL/min/1.73 m² up to 24 hr
If I want to start, what technique should I use in most cases?If I want to start, what technique should I use in most cases?
plasma clearance51Cr-EDTA3 samplessingle-exponential model (slope intercept)Jødal and Brøchner-Mortensen correction formula
plasma clearance51Cr-EDTA3 samplessingle-exponential model (slope intercept)Jødal and Brøchner-Mortensen correction formula
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
ED - ISCORN'2010 - Mikulov
INTERPRETATION: normal valuesINTERPRETATION: normal values
Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477
normal values are difficult to establish:• who is normal?• is a normal truly normal?• why carrying out a clearance measurement if a subject is normal?• which technique was used (tracer/type of clearance/technique details)• is GFR is the same in different populations?
normal values are difficult to establish:• who is normal?• is a normal truly normal?• why carrying out a clearance measurement if a subject is normal?• which technique was used (tracer/type of clearance/technique details)• is GFR is the same in different populations?
ED - ISCORN'2010 - Mikulov
INTERPRETATION : normal valuesINTERPRETATION : normal values
Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477
ED - ISCORN'2010 - Mikulov
INTERPRETATION : normal valuesINTERPRETATION : normal values
Gender difference is debated:
men : 127 ± 23 ml/min/1.73 m²women : 118 ± 16 ml/min/1.73 m² or no significant difference
Gender difference is debated:
men : 127 ± 23 ml/min/1.73 m²women : 118 ± 16 ml/min/1.73 m² or no significant difference
Blake Nucl Med Commun 2005;26:983-7.Blake Nucl Med Commun 2005;26:983-7.2-17 years: GFR= 110 ± 17 mL/min/1.73 m²2-17 years: GFR= 110 ± 17 mL/min/1.73 m²
Various normal ranges, dependant:• on technique• on tracer• on population
Various normal ranges, dependant:• on technique• on tracer• on population
ED - ISCORN'2010 - Mikulov
INTERPRETATION: : normal valuesINTERPRETATION: : normal values
Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477
in ederly people : - 1 ml/min/1.73 m² / yron the average (much scatter)
pregnancy : + 30%after eating meat
or after dopamin-hyperamine infusion : + 15-20% (glomerular reserve)nycthemeral cycle : increased during the dayafter nephrectomy : progressive recovery (50�70%)
(in ca. 6 months)
in ederly people : - 1 ml/min/1.73 m² / yron the average (much scatter)
pregnancy : + 30%after eating meat
or after dopamin-hyperamine infusion : + 15-20% (glomerular reserve)nycthemeral cycle : increased during the dayafter nephrectomy : progressive recovery (50�70%)
(in ca. 6 months)
ED - ISCORN'2010 - Mikulov
INTERPRETATION: : normal valuesINTERPRETATION: : normal values
Lines - Historical normal rangePoints – Grewal et al, 2005 Nucl Med Comm
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearance single shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
ED - ISCORN'2010 - Mikulov
INTERPRETATION: scalingINTERPRETATION: scaling
normal GFR is supposed to be proportionnal to BSAnormal GFR is supposed to be proportionnal to BSA
ED - ISCORN'2010 - Mikulov ED - ISCORN'2010 - Mikulov
INTERPRETATION: scalingINTERPRETATION: scaling
Scaling must be done to assess the degree of renal functionScaling must not be done to determine high toxicity drug dosageScaling must be done to assess the degree of renal functionScaling must not be done to determine high toxicity drug dosage
eg : a GFR of 40 mL/mineg : a GFR of 40 mL/min
in an adult of 1.73 m² BSA168 cm – 63 kg
nGFR = 40 mL/min/1.73 m²is abnormal (stage 3)
carboplatin scaled to 40 mL/min
in an adult of 1.73 m² BSA168 cm – 63 kg
nGFR = 40 mL/min/1.73 m²is abnormal (stage 3)
carboplatin scaled to 40 mL/min
in a child of 0.56 m² BSA90 cm – 12 kg
nGFR = 123 mL/min/1.73 m²is normal
carboplatin scaled to 40 mL/minNOT TO 123 mL/min (adult dosage)
in a child of 0.56 m² BSA90 cm – 12 kg
nGFR = 123 mL/min/1.73 m²is normal
carboplatin scaled to 40 mL/minNOT TO 123 mL/min (adult dosage)
=
≠
INTERPRETATION: scalingINTERPRETATION: scaling
Scaling to ECV was proposed, reducing the equations to a slope-only technique
This in only an approximation and remains quite controversial.
Scaling to ECV was proposed, reducing the equations to a slope-only technique
This in only an approximation and remains quite controversial.
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
Clinical indications for renal clearance measurementsThe concept of renal clearance
renal functionclearanceglomerular
Methods of clearance measurementstracerstypes of clearancesurinary clearancecontinuous infusion plasma clearancesingle shot plasma clearancenormalisation for body size
Practical issues in measurementChoice of MethodInterpretation
normal valuesbody size scalingcase of children
ED - ISCORN'2010 - Mikulov
INTERPRETATION: childrenINTERPRETATION: children
Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477Piepsz, Eur. J. nucl. med. mol. imag. 2006; 33:1477
ED - ISCORN'2010 - Mikulov
INTERPRETATION: childrenINTERPRETATION: children
normal GFR (2-15 years) : 104 ± 20 mL/min/1.73 m²(normal range ~ 64 – 144 mL/min/1.73 m²)
normal GFR (2-15 years) : 104 ± 20 mL/min/1.73 m²(normal range ~ 64 – 144 mL/min/1.73 m²)
considered as renal maturation(or would is just be a scaling artefact?)considered as renal maturation(or would is just be a scaling artefact?)
To conclude…To conclude…routine technique = plasma creatinine with MDRD/Schwartz formula but:• poor technique to detect renal diseases at early stage• many assay techniques, with different results• not precise (± 30 mL/min/1.73 m²)• not adapted to all patients (obese, diabetic, liver disease…)
routine technique = plasma creatinine with MDRD/Schwartz formula but:• poor technique to detect renal diseases at early stage• many assay techniques, with different results• not precise (± 30 mL/min/1.73 m²)• not adapted to all patients (obese, diabetic, liver disease…)
PoggioJ Am Soc Nephrol 200516:459
PoggioJ Am Soc Nephrol 200516:459
To conclude…To conclude…
Camera-based methods without blood sampling are not more preciseThey must be used for relative renal function assessmentDTPA/EDTA Clearance measurements* are precise (± 5 mL/min/1.73 m²)High care must be taken at all stages of the technique to get such a precisionRadiation burden is very low (~ 20 µSv for EDTA)Cold Iohexol clearance is a second-hand choice
Camera-based methods without blood sampling are not more preciseThey must be used for relative renal function assessmentDTPA/EDTA Clearance measurements* are precise (± 5 mL/min/1.73 m²)High care must be taken at all stages of the technique to get such a precisionRadiation burden is very low (~ 20 µSv for EDTA)Cold Iohexol clearance is a second-hand choice
* reference technique is bi-exponential* reference technique is bi-exponential
Question 1
What is the best index for renal function?(one choice only)
Should we normalise GFR to body size?(one choice only)
A – no, neverB – yes, always, to body surface areaC – yes, most of the time, to body surface areaD – yes, always, to body weightE – yes, most of the time, to body weight
Question 3
Should we normalise GFR to body size?(one choice only)
A – no, neverB – yes, always, to body surface areaC – yes, most of the time, to body surface areaD – yes, always, to body weightE – yes, most of the time, to body weight
Question 4
What could best characterise urine clearance measurements, as compared to plasma clearance measurements?(one choice only)
A – they are more precise and more accurateB – they are less precise but more accurateC – they are more precise but less accurateD – they are less precise and less accurateE – they are more precise and as accurate
Question 4
What could best characterise urine clearance measurements, as compared to plasma clearance measurements?(one choice only)
A – they are more precise and more accurateB – they are less precise but more accurateC – they are more precise but less accurateD – they are less precise and less accurateE – they are more precise and as accurate
Question 5
In which circumstance(s) should you perform a urinary clearance measurement instead of a plasma clearance measurement?(potentially several answers)
A – in childrenB – in patients with œdema C – in patients with hyperfiltrationD – in patients with very low renal functionE – in patients with asymetrical renal function
Question 5
In which circumstance(s) should you perform a urinary clearance measurement instead of a plasma clearance measurement?(potentially several answers)
A – in childrenB – in patients with œdema C – in patients with hyperfiltrationD – in patients with very low renal functionE – in patients with asymetrical renal function
Question 6
What is the general formula for clearance?P: plasma concentration – U: urinary concentrationBW : body weight – V : urine flow – CO : cardiac output(one choice only)
A – P × U / VB – U × V / PC – U × V / BWD – (C × O / V ) × (P / U)E – P × V × U
Question 6
What is the general formula for clearance?P: plasma concentration – U: urinary concentrationBW : body weight – V : urine flow – CO : cardiac output(one choice only)
A – P × U / VB – U × V / PC – U × V / BWD – (C × O / V ) × (P / U)E – P × V × U
Question 7
How is the plasma clearance determined?(one choice only)
A – the urinary concentration divided by the plasma concentrationB – the area under the plasma time-concentration curve divided by the injected activityC – the area under the plasma time-concentration curve divided by the plasma concentration at time 0D – the injected activity divided by the area under the plasma time-concentration curveE – the injected activity divided by the area under the plasma time-concentration curve
Question 7
How is the plasma clearance determined?(one choice only)
A – the urinary concentration divided by the plasma concentrationB – the area under the plasma time-concentration curve divided by the injected activityC – the area under the plasma time-concentration curve divided by the plasma concentration at time 0D – the injected activity divided by the area under the plasma time-concentration curveE – the injected activity divided by the area under the plasma time-concentration curve
Question 8
When using two plasma samples for plasma clearance technique:(potentially several answers)
A – two exponentials must be determinedB – one exponential only can be determinedC – a correction formula must be used, the recommended one being published by Brochner and MortensenD – a correction formula must be used, the recommended one being published by Christensen and GrothE – there is no need for correction
Question 8
When using two plasma samples for plasma clearance technique:(potentially several answers)
A – two exponentials must be determinedB – one exponential only can be determinedC – a correction formula must be used, the recommended one being published by Brochner and MortensenD – a correction formula must be used, the recommended one being published by Christensen and GrothE – there is no need for correction
Question 1
What is the best index for renal function?(one choice only)
Should we normalise GFR to body size?(one choice only)
A – no, neverB – yes, always, to body surface areaC – yes, most of the time, to body surface areaD – yes, always, to body weightE – yes, most of the time, to body weight
Question 4
What could best characterise urine clearance measurements, as compared to plasma clearance measurements?(one choice only)
A – they are more precise and more accurateB – they are less precise but more accurateC – they are more precise but less accurateD – they are less precise and less accurateE – they are more precise and as accurate
Question 5
In which circumstance(s) should you perform a urinary clearance measurement instead of a plasma clearance measurement?(potentially several answers)
A – in childrenB – in patients with œdema C – in patients with hyperfiltrationD – in patients with very low renal functionE – in patients with asymetrical renal function
Question 6
What is the general formula for clearance?P: plasma concentration – U: urinary concentrationBW : body weight – V : urine flow – CO : cardiac output(one choice only)
A – P × U / VB – U × V / PC – U × V / BWD – (C × O / V ) × (P / U)E – P × V × U
Question 7
How is the plasma clearance determined?(one choice only)
A – the urinary concentration divided by the plasma concentrationB – the area under the plasma time-concentration curve divided by the injected activityC – the area under the plasma time-concentration curve divided by the plasma concentration at time 0D – the injected activity divided by the area under the plasma time-concentration curveE – the plasma concentration at time 0 by the area under the plasma time-concentration curve
Question 8
When using two plasma samples for plasma clearance technique:(potentially several answers)
A – two exponentials must be determinedB – one exponential only can be determinedC – a correction formula must be used, the recommended one being published by Brochner and MortensenD – a correction formula must be used, the recommended one being published by Christensen and GrothE – there is no need for correction