Eur J Nutr DOI 10.1007/s00394-017-1471-6 ORIGINAL CONTRIBUTION Effect of increased water intake on plasma copeptin in healthy adults Guillaume Lemetais1 · Olle Melander2,3 · Mariacristina Vecchio1 · Jeanne H. Bottin1 · Sofa Enhörning2,4 · Erica T. Perrier1 Received: 5 August 2016 / Accepted: 6 May 2017 © The Author(s) 2017. This article is an open access publication Abstract urine osmolality and urine specifc gravity decreased from Purpose Inter-individual variation in median plasma 591 206 to 364 117 mOsm/kg (p < 0.001) and from ± ± copeptin is associated with incident type 2 diabetes mel- 1.016 0.005 to 1.010 0.004 (p < 0.001), respectively. ± ± litus, progression of chronic kidney disease, and cardio- Conclusions At baseline, circulating levels of copeptin vascular events. In this study, we examined whether 24-h were positively associated with 24-h urine concentration in urine osmolality was associated with plasma copeptin and healthy young subjects with various fuid intakes. Moreo- whether increasing daily water intake could impact circu- ver, this study shows, for the frst time, that increased water lating plasma copeptin. intake over 6 weeks results in an attenuation of circulating Methods This trial was a prospective study conducted at a copeptin. single investigating center. Eighty-two healthy adults (age Clinical Trial Registration Number NCT02044679. 23.6 2.9 years, BMI 22.2 1.5 kg/m2, 50% female) ± ± were stratifed based upon habitual daily fuid intake vol- Keywords Copeptin · Fluid intake · Hydration · Urine umes: arm A (50–80% of EFSA dietary reference values), osmolality · Water intake arm B (81–120%), and arm C (121–200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks. Introduction Results At baseline, plasma copeptin was positively and signifcantly associated with 24-h urine osmolality Vasopressin (AVP) is a peptide hormone produced in the (p 0.002) and 24-h urine specifc gravity (p 0.003) but hypothalamus that infuences body water balance by exert- = = not with plasma osmolality (p 0.18), 24-h urine creati- ing an anti-diuretic effect. Copeptin, the C-terminal seg- = nine (p 0.09), and total fuid intake (p 0.52). Over the ment of the prohormone pre-pro-vasopressin, has recently = = 6-week follow-up, copeptin decreased signifcantly from gained popularity as a surrogate marker of circulating AVP 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p 0.012), while concentration. This is due in part to the fact that the half- = life of plasma AVP is very short; copeptin, which is more stable, may, in fact, better represent plasma AVP secre- * Erica T. Perrier tion, since it is produced in a 1:1 ratio with AVP. Previous [email protected] studies have demonstrated that plasma copeptin (PCop) is 1 Hydration and Health Department, Danone Research, Route positively and independently associated with incident type Départementale 128, 91767 Palaiseau, France 2 diabetes mellitus [1–3], metabolic syndrome [4, 5], pro- 2 Department of Clinical Sciences, Lund University, Skåne gression of chronic kidney disease [6–9], and cardiovascu- University Hospital, Malmö, Sweden lar disease [10–12]. 3 Department of Internal Medicine, Skåne University Hospital, The osmotic stimulation of AVP and copeptin secretion Malmö, Sweden is well documented, and the normal physiological response 4 Department of Clinical Physiology, Skåne University is for AVP to increase in response to plasma hyperosmolal- Hospital, Malmö, Sweden ity, decreased arterial pressure, or decreased blood volume 1 3 Eur J Nutr [13]. AVP acts via V2 receptors in the nephron to increase who agreed to refrain from intensive physical activity dur- water reabsorption, trigger antidiuresis, and maintain total ing the study period (from the screening visit until the end body water homeostasis. In the literature, the osmotic of study). The exclusion criteria included following a veg- threshold for secretion has been reported as varying from etarian diet, smoking >10 cigarettes/day, excessive alcohol 280 to 295 mOsm/kg [13–15]. However, although the regu- consumption (>20 g alcohol/day), pregnancy or breastfeed- lation of AVP or copeptin secretion has been extensively ing, use of any prescription or OTC medication which may studied in situations where water balance is substantially have interfered with water balance or metabolism within challenged, such as progressive dehydration, or hemor- 14 days before the start of the study and any clinically rel- rhage, less is known about the relationship between copep- evant acute or chronic diseases. tin, urinary hydration biomarkers, and fuid intake in the Recruitment was stratifed to obtain a sample with a general population under normal daily living conditions, range of habitual fuid intake. Participants completed a where variation in water balance is more likely due to dif- 3-day electronic food and fuid diary (NutriSaas-24WQ- ferences in fuid intake. In the general population, meas- waters; MXS, France) and were subsequently allocated to ures of urine concentration have been described as well three arms based upon habitual daily fuid intake volume: suited to detect differences in the daily hydration process arm A, subjects with a fuid intake ranging from 50 to 80% [16]. Among these, 24-h urine osmolality (UOsm) and 24-h of EFSA dietary reference values for water from fuids (i.e., urine specifc gravity (USG) are positively associated with 2.0 L/day for females and 2.5 L/day for males) [23]; arm B, increased water retention by the kidney [17]. In the litera- fuid intake between 80 and 120% of EFSA dietary refer- ture, AVP was positively and signifcantly correlated with ence values; and arm C, fuid intake between 120 and 200% spot urine osmolality in healthy recumbent subjects [18]. of EFSA dietary reference values. To ensure that included A recent paper also described a higher concentration of participants were consistent in their daily drinking habits, AVP in people maintaining a 24-h UOsm above 500 mOsm/ any participant whose daily fuid intake volume varied by kg [19]. Similarly, a signifcant direct correlation was more than 25% across the three collection days was subse- described between PCop and calculated [8] or measured [20] quently excluded from the study. osmolality of spot urine, in healthy people. However, to the All participants completed a baseline visit. Next, arms best of our knowledge, it has never been demonstrated that A and B completed a 6-week water intake intervention modifying daily fuid intake can change PCop concentration designed to increase their intake to match the baseline fuid in young, healthy adults with no evidence of metabolic or intake volume of arm C. Participants in arm B were pro- renal disorders. Given the reported associations between vided with 1 L/day (women) or 1.5 L/day (men) of Evian ® elevated PCop and cardiometabolic and kidney disease, natural mineral water, while those in arm A, whose base- increased water intake may play a preventive role. As a frst line intake was the lowest, were provided with 1.5 L/day attempt to characterize this effect, we sought to investigate (women) or 2 L/day (men) in addition to their usual fuid the association between copeptin and 24-h UOsm, as well as intake. Participants were advised not to change their habit- to determine whether simply increasing daily water intake ual fuid intake except for the water provided as part of the might reduce circulating PCop. intervention. Compliance was encouraged and monitored through a daily paper log in which participants accounted for each bottle provided, and noted whether each bottle was Materials and methods fully consumed, partially consumed, or not consumed at all. These paper logs were returned to the study site every This prospective study was conducted at a single investigat- 2 weeks. Furthermore, text messaging and telephone calls ing center (Biotrial, Rennes, France) according to the ethi- were used to remind patients to follow the intervention and cal principles stated in the revised version of the Declara- complete the diaries. tion of Helsinki [21]. This is a secondary analysis of data At baseline (arms A, B, and C), and during three from a study whose primary purpose was to investigate biweekly follow-up visits ( 2, 4, and 6 weeks; arms + + + the equivalence between spot and 24-h urinary hydration A and B only), participants completed an electronic food biomarkers [22]. All subjects provided written informed and fuid diary, during the 3 days preceding the labora- consent and the study was approved by the local Ethics tory visit, collected 24-h urine samples at home the day Committee of Nancy, France (Comité de Protection des before each laboratory visit, and reported to the lab for a Personnes Est-III, Nancy, France). The study was regis- fasted morning blood draw. Urine and plasma osmolality tered on clinicaltrials.gov (NCT02044679). Subjects were were measured using a freezing point depression osmom- recruited between October 2013 and February 2014, and eter (Advanced Model 2020 Multi-Sample Osmometer; study data were collected between October 2013 and March Advanced Instruments, Inc., Norwood, MA, USA). USG 2014. This study was carried out in free-living subjects was measured with a refractometer (Pen Urine S.G., Atago 1 3 Eur J Nutr Ltd.). PCop concentration was measured in a single batch Results with a sandwich immunoassay (B.R.A.H.A.M.S. Copep- tin US Kryptor; Thermo Scientifc, Germany). Urine cre- The fnal sample included 82 participants (arm A, n 32; = atinine concentration (U ) was measured using a kinetic arm B, n 28; arm C, n 22; age 23.6 2.9 years; Creat = = ± modifcation of the Jaffe procedure using a Unicel DxI 600 BMI 22.2 1.5 kg/m2; 50% female; see Fig.