medwireNews: An international team of researchers has developed a stepwise approach to distinguishing arginine vasopressin deficiency from primary polydipsia that may shorten the diagnostic timeline, reduce unnecessary referrals, and alleviate the burden on healthcare systems.
The method starts with basal laboratory tests and rule-in and rule-out criteria to identify patients for immediate treatment. For those with intermediate laboratory findings, a clinical score provides further guidance.
“Our findings provide an efficient and practical tool, derived from routine measurements, to prioritise suspected cases for more complex testing,” write Mirjam Christ-Crain (University Hospital Basel, Switzerland) and co-authors in The Lancet Diabetes & Endocrinology.
They explain that accurately distinguishing arginine vasopressin deficiency (formerly known as central diabetes insipidus) from primary polydipsia is challenging but crucial due to the distinct treatment strategies required and the complications that can arise from misdiagnosis.
At present, “[t]here is no validated initial laboratory assessment or diagnostic score to rule-in or rule-out arginine vasopressin deficiency during the first consultation,” the researchers remark.
To address this, they used data from two international studies (CODDI and CARGOx) of patients with arginine vasopressin deficiency or primary polydipsia (>3 L/day) and hypotonic polyuria (>50 mL/kg in 24 h and urine osmolality <800 mOsm/kg) to evaluate the diagnostic potential of basal laboratory tests and develop a diagnostic score incorporating laboratory results, symptoms, and medical history.
In all, 299 patients (median age 32–45 years; 55–76% women) who underwent the hypertonic saline test between July 2013 and September 2022 were included in the analysis. Of these, 141 patients made up the development cohort (42% with arginine vasopressin deficiency; 58% with primary polydipsia) and 158 patients were in the validation cohort (44% arginine vasopressin deficiency; 56% primary polydipsia).
Christ-Crain and colleagues report that they identified “two key findings with important clinical implications for diagnosing arginine vasopressin deficiency.”
First, they show that a basal plasma sodium concentration of less than 135 mmol/L and plasma copeptin concentration of more than 5.6 pmol/L each identified patients with primary polydipsia with 100% specificity and can therefore rule out arginine vasopressin deficiency at the initial evaluation. This can enable the use of interventions such as controlled fluid intake reduction.
Conversely, a plasma sodium concentration of more than 145 mmol/L identified arginine vasopressin deficiency with 100% specificity, allowing clinicians to prescribe desmopressin after the first consultation, alongside imaging and further diagnostics to identify the underlying cause.
Second, for intermediate cases that did not meet these criteria, the researchers used machine learning-based predictors, multivariable logistic regression models, and expert-weighted clinical features to create a point-based clinical score that incorporates basal plasma sodium, plasma osmolality, plasma copeptin, nycturia (2 times or ≥3 times per night), sudden polyuria or polydipsia onset, drinking more than 1 L per night, anterior pituitary dysfunction, and pituitary surgery history.
In the validation cohort, the clinical score had an area under the receiver operating characteristic curve of 91% for the diagnosis of arginine vasopressin deficiency. This increased to 93% with the addition of magnetic resonance imaging findings, such as pituitary stalk thickening.
At a cutoff of more than 441 points, which was calculated to have the best diagnostic performance, the clinical score had an overall accuracy of 86% for diagnosing arginine vasopressin deficiency in the validation cohort.
Overall, the stepwise approach enabled diagnosis in 75% of the 299 patients.
Christ-Crain et al conclude that their method offers “a more accessible diagnostic approach for arginine vasopressin deficiency, reducing dependence on stimulation tests.”
They add: “For clinical practice, physicians can start with routine basal laboratory tests—plasma sodium and copeptin—using rule-in and rule-out criteria to guide immediate treatment initiation.
“For intermediate cases, the clinical score provides further guidance, identifying arginine vasopressin deficiency or primary polydipsia with high likelihood, ensuring that only unclear cases proceed to invasive testing.”
In an accompanying comment, Kay Weng Choy (RMIT University, Melbourne, Victoria, Australia) and Cherie Chiang (The University of Melbourne, Victoria, Australia) note that the diagnostic accuracy of the stepwise approach was “superior to the reported diagnostic accuracy of arginine stimulation and water deprivation tests.”
They add: “A key challenge in implementing the clinical score model is to ensure accessibility and ease of use in real-world clinical settings. This validated tool offers a valuable addition to diagnostic pathways and could be adapted into a web-based calculator to assist primary care physicians in prioritising referrals.”
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Lancet Diabet Endocrinol 2025; doi:10.1016/S2213-8587(25)00053-1
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