Post on 04-Sep-2019
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
• Was ist Copeptin?
• Studien
– Copeptin bei Hyponatriämie - Co-MED
– Copeptin bei Polyurie/-dipsie - CoSIP
– Copeptin bei postop. Diabetes insipides - COOP
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 für Therapiemanagement
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
Copeptin für Therapiemanagement
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
• Was ist Copeptin?
• Studien
– Copeptin bei Hyponatriämie - Co-MED
– Copeptin bei Polyurie/-dipsie - CoSIP
– Copeptin bei postop. Diabetes insipides - COOP
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
Featured Poster Presentation Number: Poster Board Number:
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
Featured Poster Presentation Number: Poster Board Number:
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
Featured Poster Presentation Number: Poster Board Number:
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).
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
Featured Poster Presentation Number: Poster Board Number:
AVP/copeptin
COOP-Studie – Resultate
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).
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).
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
Featured Poster Presentation Number: Poster Board Number:
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
Featured Poster Presentation Number: Poster Board Number:
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