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Improving Diagnosis and Treatment of Polyuria Polydipsia syndrome

English title Improving Diagnosis and Treatment of Polyuria Polydipsia syndrome
Applicant Christ-Crain Mirjam
Number 162608
Funding scheme Project funding (special)
Research institution Abteilung Endokrinologie, Diabetologie und Metabolismus Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Endocrinology
Start/End 01.10.2015 - 30.09.2018
Approved amount 678'000.00
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Keywords (1)

copeptin, vasopressin, polyuria polydipsia syndrom

Lay Summary (German)

Lead
Die genaue und verlässliche Differenzierung der Krankheitsursache eines Polydipsie-Polyurie-Syndroms (PPS) ist vor allem in Bezug auf die Therapie obligatorisch. Die Zuverlässigkeit der als Goldstandard geltenden Differenzierungs- oder Testmethoden (Bestimmung von Urinosmolalität nach Durstversuch bzw. von AVP während hypertoner Kochsalzinfusion) ist unbefriedigend. Copeptin ist ein vielversprechender Marker, der die Konzentration von AVP im Blut gut widerspiegelt. In kleineren Studien konnte mittels Copeptinmessung eine eine deutliche Verbesserung der diagnostischen Genauigkeit aufgezeigt werden. Für Patienten mit einer primären Polydipsie gibt es bisher keine Therapiemöglichkeit.
Lay summary

Ein vermehrtes Durstempfinden und Urinausscheidung kann verschiedene Ursachen haben. Dazu gehören (1) der zentrale Diabetes insipidus (DI) mit verminderter Ausschüttung des antidiuretischen Hormons (ADH) aus der Hirnanhangdrüse, (2) der renale DI, wo ADH nicht wirkt und (3) die Primäre Polydipsie (PP). Letztere ist oft das Ergebnis eines erlernten Trinkfehlverhaltens. Obgleich sich die Krankheitsbilder klinisch sehr ähnlich präsentieren, unterscheiden sich die Therapien, weswegen eine verlässliche Diagnosestellung wichtig ist. Bisher wurde für die Unterscheidung der sogenannte Durstversuch angewandt. Dabei wird die Wirkung von ADH indirekt während mehrstündigem Dursten beurteilt anhand der Konzentrationsfähigkeit der Niere. Bei einem alternativen Testverfahren wird eine Kochsalz-Infusion zur Steigerung der Blutplasmakonzentration gegeben mit Messung von ADH. Beide Testverfahren lassen aber leider keine zuverlässige Differenzierung zu.
Copeptin wird zusammen mit ADH ausgeschüttet wird und hat in kleineren Studien erfolgsversprechende Resultate in der Differentialdiagnose geliefert.
Das Ziel der ersten Studie ist es, die beiden bisherigen Testverfahren inklusive Messung von Copeptin und ADH in einer multizentrischen Studie zu prüfen und zu vergleichen. Die Hypothese ist, dass der Kochsalz-Infusionstest mit Copeptinmessung ein neuer, einfacherer Test ist mit besserer diagnostischer Zuverlässigkeit.
In einer zweiten Studie untersuchen wir, ob Copeptin nach Argininstimulation die Differentialdiagnose dieser drei Krankheitsbilder verbessert.

PP ist charakterisiert durch exzessives Trinkverhalten. Bisher gibt es keine medikamentöse Behandlungsmöglichkeiten. Nebst Wirkung auf Blutzucker und Sättigung scheint Glucagon-like-peptide 1 (GLP-1) bei gesunden Probanden einen Einfluss auf den Salz- und Wasserhaushalt zu haben mit reduzierter Trinkmenge. Das Ziel der dritten Studie ist es, zu untersuchen, ob GLP-1 Analoga eine neue Therapieoption für Patienten mit PP darstellen.

Direct link to Lay Summary Last update: 30.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.
W Fenske, J Refardt, I Chifu, I Schnyder, B Winzeler, J Drummond, A Ribeiro-Oliveira, T Drescher, S Bilz, DR Vogt, U Malzahn, M Kroiss, E Christ, M Christ-Crain (2018), A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus., in The New England journal of medicine, 428-439.
Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study".
N Nigro, B Winzeler, I Suter-Widmer, P Schuetz, B Arici, M Bally, J Refardt, M Betz, G Gashi, SA Urwyler, L Burget, CA Blum, A Bock, A Huber, M Christ-Crain (2018), Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study"., in Critical care (London, England), 1-9.
Diabetes insipidus in pregnancy: how to advice the patient?
J Refardt, M Christ-Crain (2018), Diabetes insipidus in pregnancy: how to advice the patient?, in Minerva endocrinologica, Epub-Epub.
Hyponatremia and activation of vasopressin secretion are both independently associated with 30-day mortality: results of a multicenter, observational study.
A Eckart, P Hausfater, D Amin, A Amin, S Haubitz, M Bernard, A Baumgartner, T Struja, A Kutz, M Christ-Crain, A Huber, B Mueller, P Schuetz (2018), Hyponatremia and activation of vasopressin secretion are both independently associated with 30-day mortality: results of a multicenter, observational study., in Journal of internal medicine, Epub-Epub.
Interleukin-1 Antagonism in Men with Metabolic Syndrome and Low Testosterone - A Randomized Clinical Trial.
F Ebrahimi, SA Urwyler, S Straumann, S Doerpfeld, L Bernasconi, P Neyer, P Schuetz, B Mueller, MY Donath, M Christ-Crain (2018), Interleukin-1 Antagonism in Men with Metabolic Syndrome and Low Testosterone - A Randomized Clinical Trial., in The Journal of clinical endocrinology and metabolism, Epub-Epub.
Reply to comment on: Sailer CO, et al. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy.
CO Sailer, B Winzeler, M Christ-Crain (2018), Reply to comment on: Sailer CO, et al. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy., in Swiss medical weekly, 1-1.
Artificial Syndrome of Inappropriate Antidiuresis Model as Potential Use for Diagnostic and Therapeutic Strategies.
RefardtJ, WinzelerB, MeienbergF, Christ-CrainM (2017), Artificial Syndrome of Inappropriate Antidiuresis Model as Potential Use for Diagnostic and Therapeutic Strategies., in Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 673-679.
Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia.
SailerCO, WinzelerB, NigroN, Suter-WidmerI, AriciB, BallyM, SchuetzP, MuellerB, Christ-CrainM (2017), Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia., in Clinical endocrinology, Epub-Epub.
Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data meta-analysis.
BrielM, SpoorenbergSMC, SnijdersD, TorresA, Fernandez-Serranos, MeduriGU, GabarrusA, BlumCA, ConfalonieriM, KasendaB, SiemieniukRAC, BoersmaW, BosWJW, Christ-CrainM (2017), Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data meta-analysis., in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 346-354.
Empagliflozin Increases Short-Term Urinary Volume Output in Artificially Induced Syndrome of Inappropriate Antidiuresis.
J Refardt, B Winzeler, F Meienberg, DR Vogt, M Christ-Crain (2017), Empagliflozin Increases Short-Term Urinary Volume Output in Artificially Induced Syndrome of Inappropriate Antidiuresis., in International journal of endocrinology, Epub-Epub.
Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals.
Urwyler SA, Schutz P, Ebrahimi F, Donath MY, Christ-CrainM (2017), Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals., in The Journal of Clinical Endocrinology and Metabolism, 1712-1718.
Release and Decay Kinetics of Copeptin versus AVP in Response to Osmotic Alterations in Healthy Volunteers.
WK Fenske, I Schnyder, G Koch, C Walti, M Pfister, P Kopp, M Fassnacht, K Strauss, M Christ-Crain (2017), Release and Decay Kinetics of Copeptin versus AVP in Response to Osmotic Alterations in Healthy Volunteers., in The Journal of Clinical Endocrinology and Metabolism, 505-513.

Collaboration

Group / person Country
Types of collaboration
Federal University of Minas Gerais Brazil (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Endocrinology, University hospital Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Endocrinology, University hospital Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Clinical trial Unit Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Endocrinology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Endocrinology, Kantonsspital St. Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Endocrinology, University hospital Lübeck Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Endocrinology, Cantonal hospital of Aarau Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Endocrinology, Inselspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
33th Brazilian Congress of Endocrinology and Metabolism (BCEM) Talk given at a conference Update on corticosteroid treatment in critically ill patients 09.08.2018 Belo Horizonte, Brazil Christ-Crain Mirjam;
Endocrinology Congress Talk given at a conference Copeptin as diagnostic and prognostic biomarker 25.05.2018 Milan, Italy Christ-Crain Mirjam;
DGMI Kongress Talk given at a conference Ein Patient, der viel trink und einer, der mehr trinken sollte 13.04.2018 Mannheim, Germany Christ-Crain Mirjam;
Endocrine Society's 100th Annual Meeting & Expo (ENDO 2018) Talk given at a conference Glucocorticoid treatment in pneumonia 17.03.2018 Chicago, United States of America Christ-Crain Mirjam;
BMI Symposia Talk given at a conference Stress hormones in acute and chronic disease 14.03.2018 Lausanne, Switzerland Christ-Crain Mirjam;
Hypophysen Symposium Talk given at a conference Diagnosis and treatment of SIADH 08.12.2017 Hamburg, Germany Christ-Crain Mirjam;
JADE Meeting Talk given at a conference Copeptin and diabetes insipidus 27.10.2017 Innsbruck, Austria Christ-Crain Mirjam; Refardt Julie;
8ème Journée jurassienne d’endocrinologie et de diabétologie Talk given at a conference Je bois 5 litres par jour », le diabète insipide revisté 26.10.2017 Delemont, Switzerland Christ-Crain Mirjam;
Endocrine Society Congress Talk given at a conference Diagnosis and Management of polyuria polydipsia syndrome – meet the expert 01.04.2017 Orlando, United States of America Christ-Crain Mirjam;
60. Deutsche Kongress für Endokrinologie Talk given at a conference Differentialdiagnose und Therapie des Diabetes insipidus – meet the expert 15.03.2017 Würzburg, Germany Christ-Crain Mirjam;
Swiss MedLab Congress Talk given at a conference Keynote Lecture "Labormedizin und Outcome" Titel: Hormon-Biomarker zur Outcome Verbesserung 15.06.2016 Bern, Switzerland Christ-Crain Mirjam;
18th European Congress of Endocrinology Talk given at a conference Diagnosis and treatment of diabetes insipidus 28.05.2016 München, Germany Christ-Crain Mirjam;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Wenn das Hormon fehlt, das vor Bettnässen bewahrt Basler Zeitung Western Switzerland 2018

Associated projects

Number Title Start Funding scheme
150757 Corticosteroid treatment for Community-Acquired Pneumonia - A randomized, double-blind study- The STEP trial 01.02.2014 SNSF Professorships
182753 Use of Copeptin Measurement after Arginine Stimulation for the Differential Diagnosis of Diabetes Insipidus 01.10.2018 Project funding (Div. I-III)
182753 Use of Copeptin Measurement after Arginine Stimulation for the Differential Diagnosis of Diabetes Insipidus 01.10.2018 Project funding (Div. I-III)

Abstract

Background: A variety of diseases clinically present as Polyuria Polydipsia Syndrome (PPS), i.e. central diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia. Careful differentiation of the underlying disorders is mandatory as treatment strategies vary substantially. The current “gold-standard” is the water deprivation test with indirect assessment of vasopressin (AVP) activity by measurement of the maximally reached urine osmolality during a prolonged dehydration period. However, this test is not satisfactory and often results in false diagnosis. New diagnostic procedures are urgently required. Copeptin, derived from a common pre-pro-hormone with AVP and thus mirroring its secretion, has been put forward as a promising new diagnostic marker in patients with PPS. After diagnosis is made, patients with central diabetes insipidus undergo treatment with the AVP analogue Desmopressin®. In contrast, no reasonable medical therapeutic options can be offered to patients with primary polydipsia. We therefore propose three studies: the first two (studies A and B) evaluate new diagnostic procedures in PPS and the third study (study C) evaluates a new treatment option in patients with primary polydipsia. Aims: Study A aims to replace the demanding water deprivation test by the hypertonic saline infusion test plus copeptin measurement as gold standard test method for osmotic stimulation. Study B aims to evaluate arginine infusion as a new test method to stimulate copeptin levels in PPS in order to discriminate primary polydipsia from central diabetes insipidus. Study C aims to evaluate Glucagon-like Peptide (GLP)-1 analoga as new treatment option in patients with primary polydipsia. Hypothesis: Study A: the discrimination ability between partial central diabetes insipidus and primary polydipsia of the new hypertonic saline test with copeptin measurement is not inferior to the classical water deprivation test plus copeptin measurement. Study B: Copeptin levels after arginine infusion will discriminate between patients with primary polydipsia and patients with central diabetes insipidus with a diagnostic accuracy of at least 0.8 (80%). Study C: Treatment with GLP-1 analoga in patients with primary polydipsia will lead to a 20% decrease in fluid intake as compared to a decrease of only 7% upon placebo treatment. Design: Study A: prospective multicenter international diagnostic study. Study B: prospective diagnostic pilot study. Study C: randomized placebo-controlled cross-over study. Patient population: Study A and B: Consecutive patients with PPS admitted for diagnostic evaluation. Study C: Patients with an established diagnosis of primary polydipsia. Sample size considerations: Study A: 134 patients with PPS will ensure a power of 90% to detect a positive difference of 10% from the inferiority boundary for the hypertonic saline test as significant deviation from the null-hypothesis including a 10% dropout rate. Study B: 43 patients will ensure a power of 80 % to discriminate between patients with primary polydipsia and patients with central diabetes by measuring copeptin levels after arginine infusion including a 5% dropout rate. Study C: 35 patients will ensure a power of 80 % to detect a difference in the primary endpoint (fluid intake in ml during an 8 hours period) assuming a decrease of 20% upon GLP-1 treatment compared to 7% upon placebo treatment. Collaborators and setting: Study A: Endocrine Units of 4 University hospital centers in Germany (Würzburg, Lübeck, Leipzig and Munich), 1 center in UK (Oxford), 1 center in France (Paris), one center in Ireland (Dublin) and 3 centers in Switzerland. Study B and C will be conducted at University hospital Basel, Switzerland. The Clinical Trial Unit (CTU) of the University of Basel will provide logistic and statistical support for all three studies.Significance, feasibility and outlook: The availability of reliable and simple diagnostic test methods like saline infusion or arginine infusion with copeptin measurement would significantly contribute to an important methodological simplification of the previously cumbersome diagnostic test methods of PPS, for patients and physicians alike. For patients with primary polydipsia, a treatment option with GLP-1 analoga would have a significant impact on risks (i.e. hyponatremia episodes due to drinking of high amounts of fluid despite low plasma osmolality) and on quality of life.
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