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Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study

Bettina Winzeler, Nicole Cesana-Nigro, Julie Refardt, et al

Lancet Published: July 11, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)31255-3

Summary

Background 背景

Differential diagnosis of diabetes insipidus is challenging. The most reliable approach is hypertonic saline-stimulated copeptin measurements. However, this test is based on the induction of hypernatraemia and requires close monitoring of plasma sodium concentrations. Arginine-stimulated copeptin measurements might provide an alternative, simple, and safe test.

尿崩症的鉴别诊断具有挑战性。最可靠的方法是高张盐水刺激的和肽素测定。然而，这一检查基于高钠血症的诱导作用，需要密切监测血钠水平。精氨酸刺激的和肽素测定可能成为另外一种简单安全的检查方法。

Methods 方法

In this prospective diagnostic study, we recruited a development cohort from University Hospital Basel, Basel, Switzerland, and a validation cohort from five centres in Basel, Aarau, Luzern, Bern, and St Gallen, Switzerland, and the University Hospital Würzburg, Würzburg, Germany. For both cohorts, patients were eligible for inclusion if they were aged 18 years or older, were newly referred with polyuria (>50 mL/kg bodyweight per day) or had a known diagnosis of central diabetes insipidus or primary polydipsia. We also recruited a comparator cohort of healthy controls in parallel to each cohort, comprising adults (aged 18 years and older, with normal drinking habits, and no history of polyuria) and children who underwent arginine stimulation to diagnose growth hormone deficiency (children were only included in the comparator cohort to the development cohort as proof of concept). Patients and healthy controls underwent arginine stimulation with measurement of plasma copeptin at baseline and 30, 45, 60, 90, and 120 min. The primary objective in the development cohort was to determine the diagnostic accuracy of plasma copeptin concentrations to discriminate between diabetes insipidus and primary polydipsia, and in the validation cohort was to confirm those results. Adverse effects of the test were monitored in all participants, with tolerability of the test rated using a visual analogue scale (VAS) that ranged from no (0) to maximum (10) discomfort. This trial is registered with ClinicalTrials.gov, number NCT00757276.

在这项前瞻诊断研究中，我们从瑞士Basel的Basel大学医院纳入推导队列，从瑞士Basel、Aarau、Luzern、Bern和St Gallen的5个中心，以及德国Würzburg大学医院纳入验证队列。两个队列的入选标准为年龄18岁或以上，因多尿（> 50 mL/kg体重/d）初次就诊，或已知患有中枢性尿崩症或原发性多尿。我们还针对每个队列平行纳入了健康对照比较队列，包括成年人（年龄18岁或以上，饮水习惯正常，没有多尿病史）及接受精氨酸刺激试验以诊断生长激素缺乏的儿童（儿童仅入选推导队列的对照队列以进行概念性验证）。患者与健康对照均接受精氨酸刺激，同时在基线、30、45、60、90和120分钟测定血浆和肽素水平。推导队列的主要目的为确定血浆和肽素鉴别尿崩症和原发性多尿的诊断准确性，验证队列用于确证上述结果。对于所有参研者检测不良反应，根据视觉模拟评分评价试验的耐受性，评分范围从没有（0分）到最大（10分）不适。试验在 ClinicalTrials.gov 网站注册，注册号 NCT00757276。

Findings 结果

Between May 24, 2013, and Jan 11, 2017, 52 patients were enrolled in the development cohort (12 [23%] with complete diabetes insipidus, nine [17%] with partial diabetes insipidus, and 31 [60%] with primary polydipsia) alongside 20 healthy adults and 42 child controls. Between Oct 24, 2017, and June 27, 2018, 46 patients were enrolled in the validation cohort (12 [26%] with complete diabetes insipidus, seven [15%] with partial diabetes insipidus, and 27 [59%] with primary polydipsia) alongside 30 healthy adult controls (two patients in this cohort were excluded from the main analysis because of early vomiting during the test). In the pooled patient and control datasets, median arginine-stimulated copeptin concentrations increased in healthy adult controls (from 5·2 pM [IQR 3·3–10·9] to a maximum of 9·8 pM [6·4–19·6]) and in participants with primary polydipsia (from 3·6 pM [IQR 2·4–5·7] to a maximum of 7·9 pM [5·1–11·8]), but only minimally in those with diabetes insipidus (2·1 pM [IQR 1·9–2·7] to a maximum of 2·5 pM [1·9–3·1]). In the development cohort, a cutoff of 3·5 pM at 60 min provided the highest diagnostic accuracy of 94% (95% CI 84–98). The accuracy of this cutoff in the validation cohort was 86% (95% CI 73–94). By pooling the data from both cohorts, an optimal accuracy of 93% (95% CI 86–97) was reached at a cutoff of 3·8 pM copeptin at 60 min (sensitivity 93%, 95% CI 86–98; specificity 92%, 95% CI 84–100). The test was safe and well tolerated, with median VAS scores of 3·5 (IQR 2–4) in patients with diabetes insipidus, 3 (2–4) in those with primary polydipsia, 1 (1–3) in healthy adults, and 1 (0–5) in healthy children in the pooled participant dataset.

2013年5月4日至2017年1月11日期间，共有52名患者入选推导队列（12名 [23%]完全性尿崩症，9名 [17%] 部分性尿崩症，31名 [60%] 原发性多尿），同时还纳入20名健康成人及42名儿童作为对照。2017年10月24日至2018年6月27日间，46名患者纳入验证队列（12名 [26%] 完全性尿崩症，7名 [15%] 部分性尿崩症，27名 [59%] 原发性多尿），同时纳入30名健康成人对照（其中2人因试验早期发生呕吐从主要分析中排除）。汇总患者及对照数据集后发现，健康成人对照（从5·2 pM [IQR 3·3–10·9] 升高到最大 9·8 pM [6·4–19·6]）和原发性多尿患者（从 3·6 pM [IQR 2·4–5·7] 升高到最大 7·9 pM [5·1–11·8]）精氨酸刺激后和肽素中位浓度增加，但尿崩症患者仅轻度增加（从2·1 pM [IQR 1·9–2·7] 升高到最大 2·5 pM [1·9–3·1]）。在推导队列中，以60分钟时测定和肽素水平 3·5 pM 作为临界值的诊断准确性最高，为94% (95% CI 84–98)。验证队列采用这一临界值的准确性为 86% (95% CI 73–94)。将两个队列数据汇总后，以60分钟时和肽素水平 3·8 pM 作为临界值，诊断准确性为 93% (95% CI 86–97)（敏感性93%, 95% CI 86–98; 特异性92%, 95% CI 84–100）。试验安全且耐受性良好，尿崩症患者中位 VAS 评分为 3·5 (IQR 2–4)分，原发性多尿患者为 3 (2–4) 分，健康成人为 1 (1–3) 分，健康儿童为 1 (0–5) 分。

Interpretation 结论

Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice.

精氨酸刺激和肽素测定是一种新的尿崩症诊断方法，诊断准确性高，在临床实践中可以作为一种简单安全的尿崩症诊断手段。

Funding

Swiss National Science Foundation and University Hospital Basel.

[评论]（仅代表个人观点）

• 我个人喜欢这样的研究，能够直接解决实际问题
• 相比之下，国内对于尿崩症的诊断是否过于定性，缺乏定量标准？教科书中仅仅根据尿比重，而国外常规对比血浆和尿的渗透压确定患者为低渗尿