Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland.
Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland.
Lancet. 2019 Aug 17;394(10198):587-595. doi: 10.1016/S0140-6736(19)31255-3. Epub 2019 Jul 11.
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.
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.
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.
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.
Swiss National Science Foundation and University Hospital Basel.
尿崩症的鉴别诊断具有挑战性。最可靠的方法是高渗盐水刺激加压素原测量。然而，该测试基于诱导高钠血症，需要密切监测血浆钠浓度。精氨酸刺激加压素原测量可能提供一种替代的、简单的、安全的测试方法。
在这项前瞻性诊断研究中，我们从瑞士巴塞尔大学医院招募了一个开发队列，从瑞士巴塞尔、阿劳、卢塞恩、伯尔尼和圣加仑的五个中心以及德国维尔茨堡大学医院招募了一个验证队列。对于这两个队列，如果患者年龄在 18 岁或以上，新出现多尿（>50ml/kg 体重/天）或已知中枢性尿崩症或原发性烦渴，他们有资格入组。我们还平行招募了健康对照组，包括成年人（年龄在 18 岁或以上，有正常的饮水习惯，没有多尿史）和接受精氨酸刺激以诊断生长激素缺乏症的儿童（儿童仅被纳入开发队列以证明概念）。患者和健康对照组接受精氨酸刺激，在基线和 30、45、60、90 和 120 分钟时测量血浆加压素原浓度。开发队列的主要目的是确定血浆加压素原浓度区分尿崩症和原发性烦渴的诊断准确性，验证队列的目的是确认这些结果。所有参与者都监测了测试的不良反应，并使用视觉模拟量表（VAS）来评估测试的耐受性，VAS 范围从 0（无）到 10（最大）不适。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00757276。
2013 年 5 月 24 日至 2017 年 1 月 11 日，52 名患者入组开发队列（12 名[23%]完全性尿崩症、9 名[17%]部分性尿崩症和 31 名[60%]原发性烦渴），同时入组 20 名健康成年人和 42 名儿童对照。2017 年 10 月 24 日至 2018 年 6 月 27 日，46 名患者入组验证队列（12 名[26%]完全性尿崩症、7 名[15%]部分性尿崩症和 27 名[59%]原发性烦渴），同时入组 30 名健康成年人对照（该队列中的两名患者因试验期间早期呕吐而被排除在主要分析之外）。在合并的患者和对照数据集，健康成年人对照组（从 5.2pmol/L[IQR 3.3-10.9]到最高 9.8pmol/L[6.4-19.6]）和原发性烦渴组（从 3.6pmol/L[IQR 2.4-5.7]到最高 7.9pmol/L[5.1-11.8]）的精氨酸刺激加压素原浓度中位数增加，但尿崩症患者的浓度仅略有增加（从 2.1pmol/L[IQR 1.9-2.7]到最高 2.5pmol/L[1.9-3.1]）。在开发队列中，60 分钟时 3.5pmol/L 的截值提供了 94%（95%CI 84-98）的最高诊断准确性。该截值在验证队列中的准确性为 86%（95%CI 73-94）。通过合并两个队列的数据，在 60 分钟时 3.8pmol/L 的截值达到了最佳的 93%（95%CI 86-97）准确性（敏感性 93%，95%CI 86-98；特异性 92%，95%CI 84-100）。该测试是安全且耐受良好的，在合并的患者数据集中，尿崩症患者的中位数 VAS 评分为 3.5（IQR 2-4），原发性烦渴患者为 3（2-4），健康成年人为 1（1-3），健康儿童为 1（0-5）。
精氨酸刺激加压素原测量是一种用于尿崩症的创新测试，具有很高的诊断准确性，可能是临床实践中尿崩症简化、新颖和安全的诊断方法。
瑞士国家科学基金会和巴塞尔大学医院。
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