ctproavp brief overview june 2013

8/13/2019 CTproAVP Brief Overview June 2013

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CT-proAVP (Copeptin)


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Arginine-Vasopressin (AVP)

Synonym: Vasopressin or antidiuretichormone (ADH)

Peptide hormone

Quantitative determination of AVP ischallenging:

AVP highly unstable (even at -20C)

Approx. 90% associated with platelets

!Potential use for CT-proAVP

Vasopressin

CTproAVP can be used to mirror vasopressin


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A quick review ofVasopressin(and copeptin)


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Vasopressin - Historical

1895:

Oliver and Schaffer administered a crude posterior pituitary extract to a dog which

produced an increase in arterial blood pressure Named the active ingredient: Vasopressin

1925-1936

Starling and Verney; Pickford, described the anti-diuretic effect and phyisological

action. Common name with renal physiologsists: Antidiuretic Hormone

Vasopressin

Hepatic

glycogenolysis

Corticotropin

release

Hemostasis

Vasoconstriction

Antidiursis

Central EffectsBehavioral


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Water

92% blood

75% brain

transports nutrientsand oxygen to cells

helps body to adsorb nutrients75% muscle

protects and lubricates jointseliminates toxins

helps regulate

body temperature

22% bones


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Cys

Try

Phe Gly

Asn

Cys

S-S Pro

Arg

Gly NH2


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Vasopressin Emergency Role

hypovolemia

hypotensionshock

Vasopressin

V1

Vasoconstriction

increased arterial pressure

Sudden andusually

VERY HIGHincrease ofvasopressin!


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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 theHypothalamus


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Vasopressin

Vasopressin physiological role


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Vasopressin control


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Vasopressin and Copeptin: synthesis

Produced inparaventricular nuclei ofthe hypothalamus

Stored in neurosecretory

vesicles of the posteriorpart of the pituitary gland

hypothalamus

pituitary


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sp AVP copeptinPrepropeptide

Signal peptidase

spPropeptide

Maturepeptides

1-19

asopress n-neurop ys n -copep n

AVP

Neurophysin 2

copeptinNeurophysin 21 9 13 105 107 145

AVP copeptinNeurophysin 2

copeptin:AVP = 1:1

Vasopressin and Copeptin

Copeptin can be used as a surrogate marker for vasopressin


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r = 0.78LIAAssay

Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9.

Jochberger S et al., Schock 2009 31: 132-138Validation in: Jochberger S et al., Intensive Care Med 2009 35:489-497

Correlation of Vasopressin and CT-proAVP


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Copeptin: influence food and water

man 45 yrs BMI 23 kg/m2

woman 23 yrs BMI 19 kg/m2

1 Liter within 5 min

1200 kcal over 45 min

Morgenthaler Clin Chem 2006


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Copeptin behaves like vasopressin

controlhypotonic saline

infusion

hypertonic saline

infusion

Szinnai et al. JCEM (2007)


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Morgenthaler Clin Chem 2006

men

5.2 pmol/L

gaussian

distribution

women

3.7 pmol/L

non-gaussian

distribution

Copeptin: Gender


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Role of AVP inphysiology/pathophysiology


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Morgenthaler Trends in Endocrinology & Metabolism 2007


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up to 25/30 pmol/L


Copeptin in health and disease

acute life-threateningphysiologic response cardiac

50-1500 pmol/L 20-150 pmol/L


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Vasopressin and copeptin in stress

ACTH

AVP

STRESS

Cortisol

AMI

Copeptin

If he is having a heart attack!


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Copeptin + Troponin


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Copeptin is immediately increased after AMI

Cardiac Necrosis

Troponin

rapid and accurate rule out of AMIat initial presentationwithout serial blood-sampling

Endogenous

Stress

Copeptin+

Reichlin et al JACC 2009


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Diabetes Insipidus

Polydipsia/Polyuria


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Polydipsia-polyuria syndrome

Primarypolydipsia

Central DI Nephrogenic DI Gestational DI

excessive drinking (and thirst) excessive urination


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PRIMARY POLYDIPSIA(USUALLY PSYCHOGENIC POLYDIPSIA)


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Primary Polydipsia

It is commonly associated with the sensation of having a dry

mouth When the term "psychogenic polydipsia" is used, it implies that the

condition is caused by mental disorders. However, the dry mouthis often due to phenothiazine medications used in some mentaldisorders, rather than the underlying condition.

Some forms of primary polydipsia are non-psychogenic
http://en.wikipedia.org/wiki/Phenothiazinehttp://en.wikipedia.org/wiki/Phenothiazine


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Primary polydipsia

Primarypolydipsia: occurs when vasopressin action issuppressed by excessive intake of fluids.

most common type of polyuria-polydipsia-syndrome

most often caused by an abnormality in the part of thebrain that regulates thirst or by psychogenic illnesses(psychogenic polydipsia)

difficult to differentiate from central DI because it

mimics DI.


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CENTRALDIABETES INSIPIDUS


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Central DI

tumors

infection

trauma

no (or very low)

vasopressin

cerebralbleeding

one or more steps in the production orsecretion of vasopressin is impaired

the cause if unknownin up to 50% of cases


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Central DI

Neurosurgery

- hypophysectomy

Head trauma

Idiopathic

Vascular

- cerebral hemorrhage

- cerebral thrombosis

- cerebral aneurysm

Mass lesions

- brain tumors (primary and

metastatic- histiocytosis

Infections

- meningitis

- encephalitis

Granulomas

- sarcoidosis

- tuberculosis Webeners granulomatosis

Iscemic encephalopathy

- post cardiopulmonaryresuscitation

- Sheehans syndrome(postpartum pituitarynecrosis)

Shock


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Central Diabetes insipidus (also known as neurogenic

DI): The most common type of DI is caused by deficientsecretion of vasopressin (AVP).

Treatment: various drugs including a modified vasopressinknown as desmopressin or DDAVP

Central DI


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NEPRHOGENICDIABETES INSIPIDUS

N h i DI


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Nephrogenic DI

Secondary to kidney defect which prevents formation of concentrated

urine, despite adequate vasopressin Two types

- congenital

- acquired

ADH

ADH

ADH

ADH

ADH

ADH

N h i DI


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Nephrogenic DI

Acquired

- Hypokalemia- Idiopathic

- Hypercalcemia

- Post-obstructive uropathy

- Renal tubular acidosis

- Chronic renal failure- Pyelonephritis

- Polycystic Kidney disease

Drugs

- Amphtericin B

- Gentamicin

- Colchicine

- Lithium

- Loop diuretics

Familial

- V2 receptor mutation (X-linked)- Aquaporin 2 mutation (autosomal

recessive)

N h i DI


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Nephrogenic Diabetes insipidus (also known as renal

DI): is caused by an inability of the kidneys to respond tothe "antidiuretic effect" of normal amounts of vasopressin.

Treatment: It cannot be treated with DDAVP and, dependingon the cause, may or may not be curable by eliminating theoffending drug or disease.

Nephrogenic DI


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GESTATIONALDIABETES INSIPIDUS

G t ti l DI


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ADH

ADH

ADH

ADH

ADH

ADH

Vasopressinase

XXX

Gestational DI

XXX

G t ti l DI


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Gestational DI

Gestational DI


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Gestational DI

Polyuria is often common (and expected) during pregnancy.Gestational DI is often unrecognized

(even though not very common)

Summary


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Summary

no release kidneys dont respond


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Diabetes Insipidus

Polydipsia/Polyuria

Differential Diagnosis

Differential Diagnosis of Diabetes insipidus


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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 determination of AVP release by monitoring of urineosmolality and - volume during water deprivation

(ability to concentrate urine).3. Additional Desmopressin administration to differentiatenephrogenic DI from central DI.

" Direct AVP measurement is currently notpart of the diagnosticreference standard because of its methodological limitations(instability of analyte and complicated assay handling)

Differential Diagnosis of Diabetes insipidus

Decision tree DI


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Decision tree - DI

Differential diagnosis of Diabetes insipidus status quo


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Differential diagnosis of Diabetes insipidus status quo

CentralDI

PrimaryPolydipsia

NephrogenicDI

Urine Volume/ fluidintake

Excessive Excessive Excessive

Urine-Osmolality low low low

State-of-the-art diagnosis based on a Water Deprivation Test anddesmopression intake Start the test and measure urine osmolality every hour After max. 8 hours with no fluid intake desmopressin is administered and urine

osmolality is measured for a maximum of further 8 hrs (some fluid intake allowed) After a maximum of 16 hrs end of test

CT-proAVP improves Differential diagnosis of DI


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CT proAVP improves Differential diagnosis of DI

CentralDI

Primary Polidipsia NephrogenicDI



Urine- Osmolality low low low

CT-proAVP basal (after8 hrs thirsting)

low (< 2.6 pmol/l) low(~3 pmol/l)

high(>20 pmol/l)

Diagnosis after 8 hrs fastingpossible

!Differentiation between Central and Nephrogenic DI after 8 hrs fasting over

night possible, based on CT-proAVP levels!

Basal CTproAVP: Central vs Nephrogenic DI


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Basal CTproAVP: Central vs. Nephrogenic DI

morning fasting after 8 hr fluid deprivation

CT-proAVP improves Differential diagnosis of DI


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CT proAVP improves Differential diagnosis of DI

CentralDI

Primary Polidipsia NephrogenicDI



Urine- Osmolality low low low

CT-proAVP basal (after8 hrs thirsting)

low (< 2.6 pmol/l) low(~3 pmol/l)

high(>20 pmol/l)

CT-proAVP increaseafter prolongedthirsting

(up to 16 hrs)

no yes small

!Differentiation between Central and Primary DI after 16 hrs fasting possible,based on CT-proAVP levels!

Primary Polydipsia vs. Central DI partialis


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y y p pwith Fluid Deprivation Test

16 hr fluid deprivation, 1st sample after morning fast and 8 hrfluid deprivation, 2nd sample after further 8 hr fluid deprivation

Ratio of CTproAVP increase (8-16 hr) and serum Na+ after 16 hr


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Ratio of CTproAVP increase (8-16 hr) and serum Na after 16 hr

Advantages for the diagnostic routine


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Advantages for the diagnostic routine

1. Significantly higher diagnostic accuracy

for all kinds of Diabetes insipidus and primary polydipsia

2. Substantially simplified differential diagnosis

ofpolyuria-polydipsia-syndrome

3. Reduced physical and psychological stress for patients

due to shorter fluid deprivation test and no need toadminister desmopressin

4. Savings on total costs

through reduction of labor costs and additional laboratorytest, as well as elimination of desmopressin administration

5. Reliable aid for making therapy decisions

due to highly sensitive laboratory values


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CTproAVP Assay

Characteristics

Cys

Try

Phe Gly

Asn

Cys

S-S Pro

Arg

Gly NH2

Kryptor Compact Plus


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Kryptor Compact Plus

Only Kryptor Compact Pluscan be used for theCTproAVP application

(need high sensitivity)

Available Assay technology for Diagnosis of diabetes insipidus


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FAS Kryptor

Diabetes Insipidus is no indication for theBRAHMS Copeptin KRYPTOR Assay!

Katan et al. JCEM 2007

FAS LIA FAS KCP

A h t i ti f CT AVP LIA/CT AVP KRYPTOR


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CT-proAVP LIA CT-proAVP KRYPTOR

(KRYPTOR compact PLUS)

Sample volume 50 "l 50 "l

Incubation time 2 h 14 min

Direct measuring range 0.4 - 1250 pmol/L 0.9 - 500 pmol/L

Measuring range with

automatic dilution

n.a 0.9 2000 pmol/L

Detection limit 0.4 pmol/L 0.9 pmol/L

Sample type Serum, plasma

Serum, plasma (EDTA,

heparin)

Stability 14 days (2-8C)Minimum 8 h (RT)

15 days (on board)

Calibrator n.a 1 point

Calibration stability n.a. 7 days

FAS (20% CV) < 1 pmol/L < 2 pmol/L

Assay characteristics of CT-proAVP LIA/CT-proAVP KRYPTOR

CT AVP LIA K


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CT-proAVP LIA Key messages

Stable analyte (even at room temperature)

Highest sensitivity Easy handling: one-step procedure

Time to result:


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The syndrome of inappropriate antidiuretic hormone hypersecretion(SIADH) is a condition mostly found in patients

diagnosed with small cell carcinoma of the lung, pneumonia, brain tumors, head trauma, strokes, meningitis, and encephalitis.

This is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary

gland or another source. The result is hyponatremia, and sometimes fluid overload.

ctproavp brief overview june 2013

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