A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus

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.