Hypertonic saline stimulation is superior to arginine for diagnosing AVP deficiency

1. In this prospective cohort study, hypertonic saline-stimulated copeptin was more accurate in diagnosing arginine vasopressin (AVP) deficiency than arginine-stimulated copeptin. 

2. The diagnoses made by these tests were compared against final diagnoses by two independent endocrinologists.

Evidence Rating Level: 1 (Excellent)

Study Rundown: AVP deficiency, formerly known as central diabetes insipidus, is difficult to differentiate from primary polydipsia, which is caused by excessive fluid intake despite normal AVP release and renal response. Accurate diagnosis is critical as misdiagnosis carries risks of severe complications. Copeptin is released as part of normal AVP secretion and could be measured as a surrogate marker for AVP. Hypertonic saline-stimulated copeptin has been shown in to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin is simpler to perform but lacks a head-to-head comparison with the former test. The current trial evaluated the accuracy of hypertonic saline stimulation versus arginine stimulation for diagnosing AVP deficiency among symptomatic patients and those with a previously known diagnosis. Compared to final diagnoses by two independent endocrinologists, which also included evaluation of treatment response at three months, hypertonic saline-stimulated copeptin was shown to have higher accuracy than arginine-stimulated copeptin. The majority of patients, however, preferred testing with arginine. Although the study lacked a diagnostic standard for AVP deficiency, it demonstrated that hypertonic saline stimulation was more accurate in achieving this diagnosis than arginine stimulation.

Click here to read the study in NEJM

In-Depth [prospective cohort study]: This study was a noninferiority trial to evaluate the accuracy of hypertonic saline-stimulated copeptin and arginine-stimulated copeptin tests for diagnosing AVP deficiency. Adult patients with self-reported polydipsia and measured hypotonic polyuria or those with a known AVP deficiency diagnosis were included. Exclusion criteria included AVP resistance, polyuria-polydipsia due to another cause, epilepsy, heart failure, liver cirrhosis, and critical illnesses. Overall, 158 patients were randomly assigned to undergo hypertonic saline stimulation on one day and arginine stimulation on another day. The final diagnosis was made by two independent endocrinologists after reviewing each patient’s medical history, clinical information, results of the hypertonic saline stimulation test, and response to treatment at three months. Overall, 69 (44%) of patients received the diagnosis of AVP deficiency and 89 (56%) were diagnosed with primary polydipsia. The diagnostic accuracy of the hypertonic saline stimulation test was 95.6% (95% Confidence Interval [CI] 91.1-97.8) for the prespecified copeptin cut-off of 4.9 pmol/L. The accuracy of the arginine stimulation test was 74.4% (95% CI 67.0-80.6) for the copeptin cut-off of 3.8 pmol/L at 60 minutes. Although adverse events were mild with both tests, 72% of patients preferred the arginine stimulation test to the hypertonic saline stimulation. The superiority of hypertonic saline stimulation was consistent in various other pre-specified copeptin cut-offs. A key exploratory analysis found that the arginine-stimulated copeptin level ≤3.0 pmol/L diagnosed AVP with a specificity of 90.0% (95% CI 81.7-95.7) and a copeptin value of ≥5.2 pmol/L diagnosed primary polydipsia with a specificity of 91.4% (95% CO 83.7-95.6). These results demonstrated that hypertonic saline stimulation remains superior to arginine stimulation in diagnosing AVP deficiency.

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