thermo scientific b·r·a·h·m·s ct-proavp lia for use in endocrinology february 2011
TRANSCRIPT
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Thermo Scientific B·R·A·H·M·S CT-proAVP LIA for use in endocrinology
February 2011
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Vasopressin & CT-proAVP - FAQs
What is Vasopressin (CT-proAVP) and where is it produced?
What is the physiological role of Vasopressin?
Why not simply measure Vasopressin?
Is CT-proAVP produced together with Vasopressin?
Do both analytes show the same kinetics?
Which CT-proAVP levels should be expected in normals?
Thermo Scientific B·R·A·H·M·S CT-proAVP LIA in the Differential Diagnosis of Diabetes insipidus
What about the performance of the Thermo Scientific B·R·A·H·M·S CT-proAVP LIA Assay?
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What is Vasopressin and
where is it produced?
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Structure of Vasopressin
O
NH2
NH2-
O
NH2
-C
Arginine-Vasopressin (AVP) synonym: Vasopressin or antidiuretic hormone (ADH)
peptide hormone
9 amino acids
Disulfide bridge between two cysteine amino acids
C-terminal amidation
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Synthesis of Vasopressin
Figures adapted from: Golenhofen, Basislehrbuch Physiologie, Urban & Fischer; and Morgenthaler NG et al.: Clin Chem 2006Information: Russel IC and Glover PJ: Critical Care and Resuscitation 2002; Ranger GS: IJCP 2002; Oghlakian G and Klapholz M: Cardiology in Review 2009
Synthesis as a precursor hormone
(pre-pro-vasopressin) in the hypothalamus
Cleavage and transport in granules
down the axons
Storage in granules in the posterior pituitary
Release into nearby capillaries upon
appropriate stimulation
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What is the physiological role of
Vasopressin?
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Vasopressin - physiological role
AVP:acts via V2-receptors in the kidney
-> water retention
Main role:
Regulation of water balance
Figure adapted from: Knoers NV N Engl J Med. 2005 May 5;352(18):1847-50
- Increased plasma osmolality - Decreased arterial circulating volume
AVP:Synthesis in the Hypothalamus
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receptor location effect
V2 kidney water retention
V1a vascular smooth muscle cells
strong vasoconstriction
V1b endocrine cells (e.g. pituitary)
regulation of ACTH secretion during stress
Vasopressin (AVP) effects
Effects of AVP dependent on concentration : maximal antidiuretic effect: below 15 pg/ml vasoconstrictor effect at higher concentrations very little effect on blood pressure at physiological levels!
Singh Ranger G, Int J Clin Pract 2002; 56(10):777-782
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Vasopressin in stress situation
ACTH
AVP
STRESS
Cortisol
Myocardial infarction
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Why not simply measure Vasopressin?
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Quantification of Vasopressin is difficult
Vasopressin
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Quantification of Vasopressin is difficult
Vasopressin
Vasopressin
Receptor
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Quantification of Vasopressin is difficult
Vasopressin
Platelets
Vasopressin
Vasopressin
Receptor
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Quantification of Vasopressin is difficult
Vasopressin
Platelets
Vasopressin
Protease
Vasopressin
Vasopressin
Receptor
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Quantification of Vasopressin is difficult
Vasopressin
Platelets
Vasopressin
Protease
Vasopressin
Vasopressin
Receptor
Further problem: very unstable ex vivo (even frozen)
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Quantification of Vasopressin is difficult
Vasopressin
Platelets
Vasopressin
Protease
Vasopressin
Vasopressin
Receptor
Only specialized labs measure AVP (time to results several days)Not a single FDA approved AVP assay on the market
LIMITED CLINICAL USE
Further problem: very unstable ex vivo (even frozen)
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
Signal Peptidase
Vasopressin Neurophysin II CT-proAVP
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
Signal Peptidase
Vasopressin Neurophysin II CT-proAVP
Vasopressin
ProhormoneConvertase
CT-proAVP Neurophysin II
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
Signal Peptidase
Vasopressin Neurophysin II CT-proAVP
Vasopressin
ProhormoneConvertase
CT-proAVP Neurophysin II
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
Signal Peptidase
Vasopressin Neurophysin II CT-proAVP
Vasopressin
ProhormoneConvertase
CT-proAVP Neurophysin II
CT-proAVP very stable ex vivo
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Morgenthaler NG et al., Clin Chem. 2006
Prohormone processing and assay
Signal Vasopressin Neurophysin II CT-proAVP
Signal Peptidase
Vasopressin Neurophysin II CT-proAVP
Vasopressin
ProhormoneConvertase
CT-proAVP Neurophysin II
CT-proAVP very stable ex vivo
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Is CT-proAVP produced together with Vasopressin?
Do both analytes show the same kinetics in vivo?
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r = 0.78LIA
Ass
ay
Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9.Jochberger S et al., Schock 2009 31: 132-138
Validation in: Jochberger S et al., Intensive Care Med 2009 35:489-497
Correlation of Vasopressin and CT-proAVP
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700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 18000123456789
10111213141516
Copeptin male 45 y, BMI 23
Copeptin female 23 y, BMI 19water
food
day time (hours)
Co
pep
tin
(p
mo
l/L)
t1/2: few minutes
CT-proAVP – like Vasopressin – is rapidly degraded in vivo
Morgenthaler et al. Clin Chem 2006
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700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 18000123456789
10111213141516
Copeptin male 45 y, BMI 23
Copeptin female 23 y, BMI 19water
food
day time (hours)
Co
pep
tin
(p
mo
l/L)
t1/2: few minutes
CT-proAVP – like Vasopressin – is rapidly degraded in vivo
Morgenthaler et al. Clin Chem 2006
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700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 18000123456789
10111213141516
Copeptin male 45 y, BMI 23
Copeptin female 23 y, BMI 19water
food
day time (hours)
Co
pep
tin
(p
mo
l/L)
97.5 % percentile normals:
t1/2: few minutes
CT-proAVP – like Vasopressin – is rapidly degraded in vivo
Morgenthaler et al. Clin Chem 2006
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Control Hypotonic salineinfusion
Hypertonic saline infusion / thirsting
n=8
CT-proAVP – Stimulation via osmoreceptors
CT-proAVP behaves like AVP
Szinnai et al. JCEM (2007)
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Balanescu S. et.al. JCEM 2011 in press
CT-proAVP correlates better with osmolality than Vasopressin
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0 1 2 3 4 5 6 7 8 9 10 11 12
0
100
200
300
400
500
reperfusionbleeding
baboon 157
baboon 118babbon 137baboon 150
MAP
0102030405060708090100110120130140
R21 R1R020 R4 R9
Time (hours)
CT
-pro
AV
P (
Co
pep
tin
) p
mo
l/Lm
m H
g
CT-proAVP- stimulation via baroreceptors/ hemorrhagic shock, model
CT-proAVP behaves like AVP
Morgenthaler et al. Shock 2007
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Which CT-proAVP levels should be expected in normals?
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Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9
Normal distribution
CT-proAVP is not age-related
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Bhandari SS et al, Clinical Science (2009) 116, 257–263
706 healthy volunteers
Significantly higher levels in males
CT-proAVP levels dependent on gender
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Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9
CT-proAVP: Influence of exercise
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Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9
CT-proAVP: Influence of exercise
97.5 % percentile normals:
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CT-proAVP LIA in the differential diagnosis of Diabetes insipidus
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What is Diabetes insipidus ?
• Diabetes Insipidus (DI) is a disorder in which there is an abnormal increase in urine output, fluid intake and often thirst (polyuria-polydipsia-syndrome).
• Urine output is increased because it is not concentrated normally -> the urine is not yellow but pale, colorless or watery.
• Diabetes Insipidus is divided into three types, each of which has a different cause and must be treated
differently.
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Types of Diabetes insipidus
• Central Diabetes Insipidus (also known as neurogenic DI): The most common type of DI is caused by a lack of vasopressin.
Treatment: various drugs including a modified vasopressin known as desmopressin or DDAVP
• Nephrogenic Diabetes insipidus (also known as renal DI): is caused by an inability of the kidneys to respond to the "antidiuretic effect" of normal amounts of
vasopressin.
Treatment: It cannot be treated with DDAVP and, depending on the cause, may or may not be curable by eliminating the offending drug or disease.
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Types of Diabetes insipidus
• Central Diabetes Insipidus (also known as neurogenic DI): The most common type of DI is caused by a lack of vasopressin.
Treatment: various drugs including a modified vasopressin known as desmopressin or DDAVP
• Nephrogenic Diabetes insipidus (also known as renal DI): is caused by an inability of the kidneys to respond to the "antidiuretic effect" of normal amounts of
vasopressin. Treatment: It cannot be treated with DDAVP and,
depending on the cause, may or may not be curable by eliminating the offending drug or disease. Diagnostic Challenge: All types of Diabetes insipidus also as partial forms existing!
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Types of Diabetes insipidus (II)
• primary polydipsia : occurs when vasopressin is suppressed by excessive intake of fluids.
• most common type of polyuria-polydipsia-syndrome
• most often caused by an abnormality in the part of the brain that regulates thirst or by psychogenic illnesses (psychogenic polydipsia)
• difficult to differentiate from central DI because it
mimics DI.
Interested in more?: http://www.diabetesinsipidus.orgAlso in French and Spanish language
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Clinical Challenges: Differential diagnosis of patients with polyuria-polydipsia syndrome
State-of-the art diagnosis: 1. Stimulation of AVP release via a Water deprivation test 2. Indirect measurement of AVP release by monitoring of urine
osmolality and - volume during water deprivation (ability to concentrate urine).
3. Additional Desmopressin administration to differentiate nephrogenic DI from central DI.
Direct AVP measurement becomes not the diagnostic reference standard because of its methological limitations (instability of analyte and uncomfortable assay handling)
Differential Diagnosis of Diabetes insipidus
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CT-proAVP for Differential diagnosis of Diabetes insipidus
centralDI
primary Polidipsia
NephrogenicDI
Urine Volume/ fluid intake
Excessive Excessive Excessive
Urine- Osmolality low low low
CT-proAVP basal low (< 2.6 pmol/l)
low(~3 pmol/l)
high(>20 pmol/l)
CT-proAVP increase after thirsting
no yes small
State-of-the-art diagnosis
ability to concentrate urine during water deprivation , indirect measurement via urine- volume and – osmolalityability to respond to desmopressin intake
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Differential diagnosis of Diabetes insipidus
centralDI
primary Polidipsia
NephrogenicDI
Urine Volume/ fluid intake
Excessive Excessive Excessive
Urine- Osmolality low low low
CT-proAVP basal low (< 2.6 pmol/l)
low(~3 pmol/l)
high(>20 pmol/l)
CT-proAVP increase after thirsting
no yes small
State-of-the-art diagnosis
Diagnosis without water deprivation and
Desmopressin stimulation possible!
ability to concentrate urine during water deprivation , indirect measurement via urine- volume and - osmolality
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Differential diagnosis of Diabetes insipidus
centralDI
primary Polidipsia
NephrogenicDI
Urine Volume/ fluid intake
Excessive Excessive Excessive
Urine- Osmolality low low low
CT-proAVP basal low (< 2.6 pmol/l)
low(~3 pmol/l)
high(>20 pmol/l)
CT-proAVP increase after thirsting
no yes small
State-of-the-art diagnosis
Diagnosis without water deprivation possible!
Differential diagnosis of partial
DI possible
ability to concentrate urine during water deprivation , indirect measurement via urine- volume and - osmolality
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CT-proAVP course during water deprivation
0.00 4.00 8.00 12.00 16.00 20.000
1
2
3
4
5
6
7
8
time
CT
-pro
AV
P in
pm
ol/l
Mean value of CT-proAVP in primary polydipsia
Mean value of CT-proAVP in central DI
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Superiority of CT-proAVP in diagnosing Diabetes insipidus
Conclusion: Current state-of -the art - method WDT gives no reliable results in the differential diagnosis of polyuria-polydipsia syndrome!CT-proAVP is superior to the current method of choice and revives the concept of the direct test in the polyuria- polydipsia syndrome.
Fenske W. et.al. Copeptin in the differential diagnosis of the polyuria- polydipsia syndrome – revisiting the direct and indirect water deprivation tests. JCEM accepted January 2011
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CT-proAVP: Diagnosis of central DI totalis and nephrogenic DI in the 1st blood draw
Fenske W. et.al. Copeptin in the differential diagnosis of the polyuria- polydipsia syndrome – revisiting the direct and indirect water deprivation tests. JCEM accepted January 2011
basal CT-proAVP [pmol/l] (fasting, in the morning after 8h
dehydration)
< 2.6 >20
Sensitivity (%) 95 100
Specificity (%) 100 100
Central Diabetes nephrogenic
insipidus totalis Diabetes insipidus
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Best separation of primary polydipsia and partial central DI (in contrast to current methods including AVP measurements)
specificity 100%sensitivity 86%
Poster:Fenske W: 14th Annual meeting of the neuroendocrinology section of the DGEOctober 15, 2010 (Munich)
Paper accepted at JCEM Jan. 2011
Differential diagnosis of unclear cases after water deprivationer
um
-N
a+
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Index
Δ CT-proAVP [8h-16h] x 1000 [pmol/L/mmol/L]
S-Na+ [16h]
<20 >20
Sensitivity (%) 100 86
Specificity (%) 86 100
central Diabetes primary insipidus partialis polydipsia
2nd blood draw: Stimulated CT-proAVP differentiates safe between central DI partialis and Primary Polydipsia
Fenske W. et.al. Copeptin in the differential diagnosis of the polyuria- polydipsia syndrome – revisiting the direct and indirect water deprivation tests. JCEM accepted January 2011
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Reliable differential diagnosis of DI with the help of CT-proAVP
Suspicion of Diabetes insipidus with Polyurie-Polydipsie-Syndrome
CT-proAVP basal (in the morning, fasting, after 8h dehydration)
CT-proAVP<2,6 pmol/L
CT-proAVP>20 pmol/L
Central Diabetes insipidus totalis
Renal Diabetes insipidus
CT-proAVP>=2,6 - 20 pmol/L
CT-proAVP-Index<20
CT-proAVP-Index>=20
Central Diabetes insipidus partalis
Primary Polydipsia
Ratio of CT-proAVP-Delta (8 to16h) and Serum-Na+ (16h) = CT-proAVP-Index
CT-proAVP stimulated and Serum-Na+ (after 16 hours dehydration)
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Advantages for the diagnostic routine
• Significantly higher diagnostic accuracy for all variations of Diabetes insipidus and primary Polydipsia
• Considerably eased differential diagnosis of Polyuria-Polydipsia-Syndrome
• Reduced physical and psychical exposure of the patient due to simplified WDT and redundancy of desmopressin stimulation
• Support of safe therapeutic decisions with highly sensitive measurement values
• Overall cost reduction due to reduced complexity, less lab consulting and no prescription of desmopressin
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What about the performance of the LIA assay?
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Reminder: Why not measure AVP directly?
• AVP is very unstable in plasma even at -20 °C storage (sample transport frozen or blood collection directly in the lab)
• AVP is largely attached to platelets• AVP assays performed with the required accuracy are available
in only a few selected laboratories (non of them FDA cleared)
• Sample extraction necessary
• Time to result up to 72 hours
• Sample volume 1-4 ml plasma
• No reliable clinical results
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Advantages Thermo Scientific B·R·A·H·M·S CT-proAVP LIA
• sample volume only 50µl
• for plasma and serum
• one-step procedure (time to result 3 hours)
• stable analyte (at room temperature)
• highest sensitivity
• sandwich-immunoassay
• clinical superiority shown
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CT-proAVP LIA assay parameters
Sample type serum, plasma
Volume 50 µl
Incubation time 2 hours
Stability at RT minimum 8 hours
Stability at 2-8°C 14 days
Freezing and thawing No influence up to 3 cycles
Analytical assay sensitivity < 0,4 pmol/L
FAS (20% CV) < 1 pmol/L
Direct measuring range 0,4 - 1250 pmol/L
Data taken from IFU (instructions for use)