Arginine-stimulated copeptin was inferior to hypertonic saline-stimulated copeptin in the diagnosis of arginine vasopressin (AVP) deficiency, formerly known as central diabetes insipidus, the CARGOx trial showed.
Of 158 patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency who underwent both tests, diagnostic accuracy was 74.4% (95% CI 67.0-80.6) for arginine-stimulated copeptin and 95.6% (95% CI 91.1-97.8) for hypertonic saline-stimulated copeptin, reported Julie Refardt, MD, PhD, of University Hospital Basel in Switzerland, and colleagues.
Notably, 72% of the patients preferred testing with arginine as compared with hypertonic saline, they wrote in the New England Journal of Medicine.
Though adverse events were generally mild for both tests, the most common side effects were thirst, mild headache, and vertigo, which were more intense and more frequent with the hypertonic saline test.
However, while the arginine-stimulation test is simpler and has a better side-effect profile than the hypertonic saline test, its reliability has been in question, noted John Newell‑Price, PhD, of the University of Sheffield in England, in an accompanying editorial.
“The arginine-stimulation test is straightforward in that it requires a short intravenous infusion and sampling at 60 minutes for copeptin,” he explained. “In contrast, the hypertonic-saline test is more cumbersome and requires bolus doses, longer infusions, and repeated testing of venous samples for plasma or serum sodium levels until the levels reach more than 149 mmol per liter, at which point sampling for copeptin is performed.”
Because hypertonic saline is an irritant, it also requires good venous access for administration. On top of that, some of the fluid loads and electrolyte shifts associated with it may be contraindicated in some patients, such as those with heart failure or epilepsy.
“Given the simplicity of the arginine-stimulation test, it is a shame that it was found to be inferior,” Newell-Price wrote.
Refardt told MedPage Today that though simplicity and side effects may be a trade-off, having a reliable diagnostic test is important for the correct treatment and avoidance of potentially serious side effects due to a wrong diagnosis. “If executed correctly, [hypertonic saline-stimulated copeptin] is also a safe test. Nevertheless, arginine stimulation can still be used as a first simple test to diagnose over half of the patients.”
Newell-Price added that physicians should keep their patients in mind when using these tests in clinical practice. “Not every patient who presents with hypotonic polyuria needs to undergo stimulation testing,” he wrote. “For example, in patients with pituitary or hypothalamic disease, especially with mild hypernatremia, the diagnosis of partial or complete AVP deficiency is highly likely, and an analysis of matched plasma and urine osmolalities or basal copeptin levels may be sufficient for diagnosis.”
On the other hand, for patients with no prior diagnosis or contraindications, hypertonic saline is the way to go in order to differentiate between AVP deficiency and primary polydipsia, he noted.
For this international noninferiority study, 158 patients (67% women) underwent diagnostic evaluation with hypertonic saline stimulation on one day and with arginine stimulation on another day. These copeptin tests, featuring a polypeptide that is released as part of normal AVP secretion, were established after the once commonly used indirect water deprivation test was found to have low diagnostic accuracy.
The final diagnoses, made by two endocrinologists 3 months after the tests, were based on prespecified cutoff levels for copeptin of 3.8 pmol/L after 60 minutes for arginine and 4.9 pmol/L once the sodium level was more than 149 mmol/L for hypertonic saline.
A stimulated copeptin level less than 2.7 pmol/L indicated complete AVP deficiency, a level of 2.7 to 4.9 pmol/L indicated partial AVP deficiency, and a level of more than 4.9 pmol/L indicated primary polydipsia.
Of the 158 patients who underwent the two tests, 44% were diagnosed with AVP deficiency and 56% were diagnosed with primary polydipsia.
“Exploratory analyses of data-derived best copeptin cutoff values did not reveal any material difference in performance,” the authors noted.
However, an arginine-stimulated copeptin at a value of 3.0 pmol/L or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI 81.7-95.7), while levels of more than 5.2 pmol/L led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI 83.7-95.6).
The study was funded by the Swiss National Science Foundation.
Refardt and co-authors reported relationships with the Goldschmidt Jacobson Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Ipsen Pharma SAS, Novartis, Serb, Cambridge University Hospitals NHS Foundation Trust, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, the Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.
Newell-Price reported relationships with the Endocrine Society.
New England Journal of Medicine
Source Reference: Refardt J, et al “Arginine or hypertonic saline-stimulated copeptin to diagnose AVP deficiency” N Engl J Med 2023; DOI: 10.1056/NEJMoa2306263.
New England Journal of Medicine
Source Reference: Newell-Price J “Testing for arginine vasopressin deficiency” N Engl J Med 2023; DOI: 10.1056/NEJMe2311293.