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A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus
Open accessAbstract
BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).
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TL;DR
In 141 analyzed patients with hypotonic polyuria, hypertonic saline–stimulated plasma copeptin measurement was more accurate than the indirect water-deprivation test for distinguishing central diabetes insipidus from primary polydipsia. The prespecified copeptin cutoff of >4.9 pmol/L achieved 96.5% overall diagnostic accuracy versus 76.6% for the indirect water-deprivation test.
Key findings
- Hypertonic saline–stimulated copeptin (>4.9 pmol/L) correctly diagnosed 136 of 141 patients (96.5%; 95% CI, 92.1–98.6), compared with 108 of 141 (76.6%; 95% CI, 68.9–83.2) for the indirect water-deprivation test (P<0.001).
- For the clinically important distinction of primary polydipsia from partial central diabetes insipidus, accuracy was 95.2% (99/104; 95% CI, 89.4–98.1) with hypertonic saline–stimulated copeptin versus 73.3% (77/105; 95% CI, 63.9–81.2) with the indirect water-deprivation test (adjusted P<0.001).
- At the prespecified >4.9 pmol/L cutoff, sensitivity was 93.2% and specificity 100%; a post hoc >6.5 pmol/L cutoff had diagnostic accuracy 97.9%, sensitivity 94.9%, and specificity 100%.
- Water-deprivation–stimulated copeptin had lower diagnostic accuracy than the indirect water-deprivation test (44.0%; 95% CI, 35.7–52.5 vs. 76.6%; 95% CI, 68.9–83.2), and one serious adverse event occurred during water deprivation: desmopressin-induced hyponatremia requiring hospitalization.
Methods
- Prospective, international, multicenter study at 11 tertiary medical centers in Switzerland, Germany, and Brazil from July 2013 to June 2017; 156 patients aged ≥16 years with hypotonic polyuria or confirmed central diabetes insipidus were recruited, 144 underwent both tests, and 141 were included in the primary analysis.
- Patients underwent an indirect water-deprivation test and a hypertonic saline infusion test on separate days; plasma copeptin was measured when plasma sodium reached at least 150 mmol/L after hypertonic saline.
- Primary outcome was overall diagnostic accuracy versus a final reference diagnosis determined after study completion by two independent board-certified endocrinologists masked to copeptin levels, using medical history, water-deprivation test results, laboratory and imaging data, and 3-month treatment response; discordant diagnoses (4 of 144) were resolved with a third expert.
Limitations
- The paper states there is no diagnostic standard for hypotonic polyuria and that the reference diagnosis incorporated indirect water-deprivation test results, which may have caused incorporation bias; if present, this may have overestimated the diagnostic performance of the water-deprivation test.
- The paper notes caveats for hypertonic saline infusion: more adverse effects were reported than with water deprivation, close sodium monitoring was required, and female patients appeared more vulnerable to marked sodium increases; the test also required achieving a diagnostically meaningful hyperosmotic sodium level.
- Evident from the text: nephrogenic diabetes insipidus was assessed only descriptively in 3 patients, so performance in that group is not established; symptom burden and preference relied on patient-rated visual-analogue scores.
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“One serious adverse event was reported: desmopressin-induced hyponatremia after the water-deprivation test, which resulted in hospitalization of the patient (Table 3).”
plainstates a causeSingle case- Asserted: passes — The authors put it forward as true.
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“and the overall tolerability (i.e., convenience of the test and patients' comfort level during the test) lower (38% of patients preferred the water-deprivation test, whereas 62% preferred the hypertonic saline infusion test)”
plainstates an association- Asserted: passes — The authors put it forward as true.
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“However, the postulated superiority of water-deprivation-stimulated copeptin to the indirect water-deprivation test could not be confirmed in this study.”
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“All the patients in the current study whose diagnosis was misclassified according to the indirect waterdeprivation test received the correct diagnosis according to the results of the hypertonic saline infusion test with the prespecified copeptin cutoff of 4.9 pmol per liter.”
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“The overall diagnostic accuracy of waterdeprivation-stimulated copeptin (with use of the prespecified ratio of stimulated copeptin to plasma sodium described above) in distinguishing primary polydipsia from central diabetes insipidus 5 was significantly lower than that of the indirect water-deprivation test (44.0%[95% CI, 35.7 to 52.5] vs. 76.6% [95% CI, 68.9 to 83.2])”
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“Shivering 1 (<1) 3 (<1)”
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“67.1 (55.4-77.5)57/76”
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“Hyponatremia due to excess water retention after administration of desmopressin 4 (<1)”
Reported 1 · recomputed 2.836879
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Metadata
- Authors
- Fenske, W., Refardt, J., Chifu, I., Schnyder, I., Winzeler, B., Drummond, J., Ribeiro-Oliveira, A., Drescher, T., Bilz, S., Vogt, D. R., Malzahn, U., Kroiss, M., Christ, E., Henzen, C., Fischli, S., Tönjes, A., Mueller, B., Schopohl, J., Flitsch, J., Brabant, G., Fassnacht, M., & Christ-Crain, M.
- Affiliations
- University of Würzburg (DE)
- Universidade Federal de Minas Gerais (BR)
- From the University of Leipzig, Department of Endocrinology and Nephrology (W.F., A.T.), and Leipzig University Medical Center, Integrated Research and Treatment Center Adiposity Diseases (W.F.), Leipzig, the Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg (I.C., M.K., M.F.), and the Clinical Trial Center (U.M.) and Central Laboratory (M.F.), University Hospital Würzburg, Würzburg, Medizinische Klinik und Poliklinik IV, Ludwig...
- University of Basel (CH)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-08-02
- Volume
- 379
- Issue
- 5
- Pages
- 428-439
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2886697375
- Semantic Scholar
- a39acf4d43bf7ce8825c5447520285c5c1bf2340
- Cited by
- 310
- References
- 40
- Citations by year
- 2026: 30 · 2025: 53 · 2024: 41 · 2023: 33 · 2022: 34 · 2021: 52 · 2020: 29 · 2019: 25 · 2018: 11
- FWCI
- 24.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Thermo Fisher Scientific (none, laboratory measurement of copeptin)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF-162608)
- Deutsche Forschungsgemeinschaft (AOBJ: 624808)
- Bundesministerium für Bildung und Forschung (FKZ:01EO1501)
- Topics
- Health Sciences › Medicine › Nephrology › Electrolyte and hormonal disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- copeptin, water deprivation test, vasopressin, central diabetes insipidus, nephrogenic diabetes insipidus, primary polydipsia, diagnostic accuracy
- MeSH terms
- Adult, Deamino Arginine Vasopressin, Diabetes Insipidus, Diagnosis, Differential, Female, Glycopeptides, Humans, Hyponatremia, Male, Middle Aged, Osmolar Concentration, Polyuria, ROC Curve, Saline Solution, Hypertonic, Sensitivity and Specificity, Urine, Water Deprivation, Polydipsia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-14, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
