copeptin - universitätsspital basel · water and electrolyte disturbances and patients with a...

Bettina Winzeler und Nicole Nigro Abteilung für Endokrinologie, Diabetologie und Metabolismus

Copeptin

Research Lunch 25.03.2014

Heutiges Programm

• Was ist Copeptin?

• Studien

– Copeptin bei Hyponatriämie - Co-MED

– Copeptin bei Polyurie/-dipsie - CoSIP

– Copeptin bei postop. Diabetes insipides - COOP

Was ist Copeptin?

Pre-Pro-Vasopressin (Prohormon)

Vasopressin / AVP

AVP

Copeptin

Hypernatriämie

Hyperosmolarität

Hypotonie

Hypovolämie

Stress (OP, Krankheit,

Erbrechen etc.)

Copeptin bei akuten Erkrankungen

Christ-Crain et al., Eur J Clin Invest 07, Morgenthaler et al., Shock 07 Katan et al., Ann Neurol 09, Reichlin et al., JACC 09

Balanescu et al., JCEM 2011

Copeptin wiederspiegelt AVP Veränderungen nach Osmolaritätsanstieg

co

pe

ptin

AVP

R = 0.80

p < 0.001

Szinnai G et al., JCEM 2007

AVP / Copeptin

AVP

Copeptin

Hypernatriämie

Hyperosmolarität

Hypotonie

Hypovolämie

Stress (OP, Krankheit,

Erbrechen etc.)

Hyponatriämie

Heutiges Programm


• Studien




Hyponatriämie-Background

• Häufige Elektrolytstörung im Spital

• Assoziiert mit höherer Morbidität und Mortalität

• Differentialdiagnose schwierig

• Therapieverzögerung?

Copeptin als neuer Biomarker?

Adrogue H, NEJM, 2001 Upadhyay A, Am J of Med 2006 Ellison DH, NEJM, 2007 Zilberberg M, Curr Med Res Opini 2008

Die Co-MED Studie

• Prospektive, multizentrische Observationsstudie

• Einschlusskriterien: schwere hypoosmolare Hyponatriämie (<125mmol/L)

• Copeptin bei Eintritt und nach Normalisierung Na+

• Standardisierte diagnostische Evaluation mittels Algorithmus

• Ziel:

- Validierung des Copeptins in der

Differentialdiagnose der schweren Hyponatriämie

- Therapiemanagement mit Copeptin

General information

Age (years) 71 (60-80) Female n (%) 195 (65%) Laboratory parameters Plasma sodium (mmol/L) 120 (116-123) Copeptin (pmol/L) 15.98 (6.01-38.87) Comorbidities Hypertension n (%) 200 (67%) CNS diseases n (%) 114 (38%) Previous dysnatremia n (%) 126 (42%) Congestive heart failure n (%) 44 (15%) Renal failure n (%) 64 (21%) Pulmonal diseases n (%) 83 (28%) Volemic status

- Hypovolemic n (%) 83 (28%)

- Euvolemic n (%) 173 (58%)

- Hypervolemic n (%) 43 (14%)

Medication

Loop diuretics 56 (19%)

Thiazid diuretics 129 (43%)

Potassium sparing diuretics 34 (11%)

Baseline characteristics (n=298)

Copeptin in der DD der Hyponatriämie

Primar

y poly

dipsia

(n =

24)

Cort

isol d

efic

iency

(n =

4)

SIAD (n

= 1

06)

Diu

retic

-induce

d (n =

72)

Hyp

ervo

lem

ic h

yponatre

mia

(n =

33)

Hypovole

mic

hyp

onatrem

ia (n

= 5

9)0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100200400600800

10001200

Pla

sm

a C

op

ep

tin

lev

els

pm

ol/L

P < 0.0001

Copeptin für Therapiemanagement

Fluid

res

tric

tion (n

= 1

59)

Sal

ine

infu

sion (n

= 1

39)

0

10

20

30

40

50

60

70

80

90

100

200

400

600

800

1000

1200

1400

Pla

sm

a C

op

ep

tin

lev

els

pm

ol/L

P = 0.004


Copeptin >56.8 pmol/L: Specificity: 85.4%

Copeptin <4.4 pmol/L: Specificity: 90.4%

Copeptin für Therapiemanagement- Multivariate Analyse

Odds Ratio 95% CI P levels

FEurea 0.98 0.96- 1.00 0.042

Volume status 0.29 0.17- 0.49 0.001

FEuric acid 0.94 0.90- 0.98 0.008

Urinary sodium 1.00 0.99 - 1.01 0.532

Copeptin 1.19 1.07- 1.32 0.002

Urinary

osmolality

1.00 1.00- 1.00 0.764

0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

Se

ns

itiv

ity

0.00 0.25 0.50 0.75 1.00

Specificity

SCORE1 ROC: 0.77 FEHSR ROC: 0.67

VOLUME ROC: 0.67

COPEPTIN ROC: 0.62


Zusammenfassung

• CopeptinSurrogatmarker von AVP

• Copeptin mässig hilfreich bei Hyponatriämie

• Copeptin >57pmol/L (Spez. für Volumengabe: 86%), Copeptin < 4.5pmol/L (Spez. für Flüssigkeitsrestriktion: 91%)

– Therapievereinfachung?

• Kombination von FeHRS, Volumenstatus und Copeptin verbessert Therapiemanagement

Heutiges Programm


• Studien




ADH

• ->

Diabetes insipidus

AVP

Polyuria >50ml/kg KG/24h

Zentral

Nephrogen

DD: Primäre Polydipsie

• DD:

– Zentraler (komplett or partiell) DI (AVP Mangel)

– Nephrogener (komplett or partiell) DI (AVP Resistenz)

– Primäre Polydipsie

Durstversuch

Abklärung Polyurie / Polydipsie

Urinkonzentration-Fähigkeit?

AVP?

CoSIP Studie

• Prospektive multizentrische Observatiosstudie (Basel,

Aarau, Bern, Würzburg)

• N= 52

• Standardisierter Durstversuch

• falls Natrium nicht >147mmol/L -> 3% NaCl Infusion

• regelmässige Messung von Copeptin

>20 pmol/L

COSIP – Baseline Copeptin

Baseline Copeptin >20pmol/L → 100% Sensitivität & Spezifität für nephrogenen DI

P < 0.0001

≤2 pmol/L

Delta-Copeptin

= Copeptin (P-Na>147) –

baseline copeptin)

COSIP – Stimuliertes Copeptin

Delta-copeptin ≤2pmol/L → 94% Sensitivität & 96% Spezifität für DD zentraler DI / Primäre Polydipsie

AVP / Copeptin Triggers

Hyponatremia Hyperosmolarity Hypotension Hypovolemia

Arginin Vasopressin ↑

Vasoconstriction

Increased H2O absorption

Stress

Hypoglykämie = Stress!

Copeptin b

asal

30 min

45 min

90 min

0

5

10

15

20

25

Cop

eptin

(pm

ol/L

)

Intakte Neurohypophyse Copeptin

basal

30 min

45 min

90 min

0

5

10

15

20

25

Cop

epti

n (p

mol

/L)

Diabetes insipidus

Katan et al., J Clin Endocrinol Metab, 2007

Copeptin - Insulin Hypoglykämie Test

DISCLOSURES:

Featured Poster Presentation Number: Poster Board Number:

Akute Störungen des Wasser - und Salzhaushalts nach Hypophysenoperation

Singer PA, Neurosurg Clin N Am (2003) Black PM, Neurosurgery (1987)

Hensen J, Clin Endocrinol (1999)

preop.

2h p

ostop.

8h p

ostop.

24h p

ostop

0

10

20

30

time

co

pe

ptin

(p

mo

l/l) normal n= 79

DI n= 25

Diabetes insipidus (DI) ≈ 20% SIADH ≈ 5%

DISCLOSURES: COPEPTIN


Diabetes insipidus – Arginin Vasopressin (AVP) und Copeptin

AVP Szinnai G et al., JCEM (2007)

Balanescu et al., JCEM (2011)

COSIP – Baseline Copeptin

AVP / Copeptin Triggers

Hyponatremia Hyperosmolarity Hypotension Hypovolemia

Arginin Vasopressin ↑

Vasoconstriction

Increased H2O absorption

Stress

Durstversuch

Katan et al, Neuroendocrinol Lett (2008)

Operation = Stress! Stress


COOP-Studie

DISCLOSURES:

AVP/copeptin

Hypothese: Fehlender Copeptinanstieg trotz Operations-Stress bei Patienten, welche im Verlauf einen DI entwickeln

Ziel: Evaluation von Copeptin als Marker für den postoperativen DI


AVP/copeptin

COOP-Studie

Setting: Patients admitted for transsphenoidal or transcranial pituitary surgery to the University Hospital of Basel and Medical University Clinic of Aarau are prospectively observed. Herein we present preliminary data of an on-going study evaluating copeptin levels of patients with an uneventful postoperative course in terms of water and electrolyte disturbances and patients with a postoperative Diabetes insipidus (DI).

Work-up on admission: •From the preoperative day to the day of discharge patients were daily monitored for clinical items (i.e. vital signs, balance of fluids) and routine laboratory parameters. •Copeptin levels were measured preoperatively, within 0-24 hours after surgery and daily until discharge. •Tumour specific features and intraoperative manipulation of the neurohypophysis were recorded.

Diagnosis of DI: The diagnosis of DI was made retrospectively by an independent expert panel after complete chart review. Diagnostic criteria included clinical signs and symptoms (polyuria > 50 ml/kg/d) and typical laboratory findings (sodium > 145 mmol/l, serum osmol. > 295 mosmol/l, urine osmol. < 400-800 mosmol/l).




Diabetes insipidus n = 50 (24,4%) kein Diabetes insipidus n = 155

• Prospektive multizentrische Beobachtungsstudie

• 205 Patienten vor Hypophysenoperation

• Copeptin präop., < 24 Std. postop. und tägl. bis Austritt

Total n=205 No diabetes insipides n=155 (75,6%)

Diabetes insipides n=50(24,4%)

P value

Age (years) [IQR] 55 [44;67] 53 [39;64] 0.34

Female sex (%) 85 (54.8%) 29 (58.0%) 0.75

Hormone Inactive adenomas 85 (54.8%) 13 (26.0%) 0.0005

Somatotroph adenomas 15 (10.0%) 3 (6.0%) 0.57

Corticotroph adenomas 11 (7.1%) 3 (6.0%) 1.00

Gonadotroph adenomas 1 (0.7%) 0 1.00

Prolactinoma 6 (4.0%) 2 (4.0%) 1.00

Rathke‘s Cleft Cyst 6 (4.0%) 11 (22.0%) 0.0003

Craniopharyngioma 2 (1.3%) 7 (14.0%) 0.0009

Meningioma 11 (7.1%) 2 (4%) 0.74

Apolexy 7 (4.5%) 1 (2.0%) 0.68

Other 11 (7.1%) 8 (16.0%) 0.09

Tumor Diameter (mm) [IQR] 24 [18; 29] 19 [14; 25] 0.014

Transsphenoidal Surgery (% vs. Transcranial) 141 (91%) 45 (90%) 0.79

Intraoperative CSF Leak 21 (13.5%) 14 (28.0%) 0.029

Patienten Charakteristika


AVP/copeptin

COOP-Studie – Resultate







0 12 24 36 480

10

20

30

minutes

co

pep

tin

(p

mo

l/l)

normal n = 155

DI n = 50

copeptin values no DI (155) DI (50) P value

preop. (pM, median [IQR]) 3.92 [2.5-6.5] 2.9 [1.9-4.7] 0.04

postop. (pM, median [IQR]) 10.8 [5.2-30.4] 2.9 [1.9-7.9] <0.001

DI n = 50 (24,4%) kein DI n = 155

Stunden


DISCLOSURES:

AVP/copeptin

0

10

20

30

40

50

60

70

80

90

100

<2.5 pmol/l 2.5-5 pmol/l 5-10 pmol/l 10-20 pmol/l 20-30 pmol/l >30 pmol/l

Inci

de

nce

of

Dia

be

tes

insi

pid

us

(%)

All patients

Copeptin measurement <12 hour

DI-Risiko anhand Copeptinwerten


DISCLOSURES:

AVP/copeptin

Assoziation Copeptinwerte und Entwicklung DI

0.0

0

0.2

5

0.5

0

0.7

5

1.0

0

Sensitiv

ity

0.00 0.25 0.50 0.75 1.00 1 - Specificity

Copeptin postop. (n=205) AUC 0.79 Copeptin < 12h postop (n=157) AUC 0.84

Diagnostische Performance von Copeptin

Zusammenfassung

• Polyurie-Polydipsie-Syndrom: basales Copeptin Nephrogener DI osmotisch stimuliertes Copeptin verbessert Diagnostik • Postoperativer Diabetes insipidus Operationsbedingter Copeptinanstieg unauffälliger Verlauf Tiefes Copeptin trotz Operations-Stress DI

Danke…

• Birsen Arici • Ingeborg Wegner • Christian Zweifel • Chris Kelly • Hans Landolt • Mirjam Christ-Crain

• Martina Bally • Claudine Blum • Philipp Schütz • Beat Müller • Luigi Mariani

copeptin - universitätsspital basel · water and electrolyte disturbances and patients with a...

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