Hydration for health hypothesis: a narrative review of supporting evidence

Abstract

PurposeAn increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration.Methods
Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied.ResultsThe available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease.Conclusion
In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day−1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg−1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake.

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European Journal of Nutrition (2021) 60:1167–1180
https://doi.org/10.1007/s00394-020-02296-z
REVIEW
Hydration forhealth hypothesis: anarrative review ofsupporting
evidence
EricaT.Perrier1· LawrenceE.Armstrong2,3· JeanneH.Bottin1· WilliamF.Clark4· AlbertoDolci1·
IsabelleGuelinckx1· AlisonIroz1· StavrosA.Kavouras5· FlorianLang6· HarrisR.Lieberman7· OlleMelander8·
ClementineMorin1· IsabelleSeksek1· JodiD.Stookey9· IvanTack10· TiphaineVanhaecke1· MariacristinaVecchio1·
FrançoisPéronnet11
Received: 24 February 2020 / Accepted: 28 May 2020 / Published online: 6 July 2020
© The Author(s) 2020
Abstract
Purpose An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short-
and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration
remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that
optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of
optimal hydration.
Methods Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, comple-
mented by manual search of article reference lists and the expertise of relevant practitioners for each area studied.
Results The available literature suggest the effects of increased water intake on health may be direct, due to increased urine
flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects
the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in
metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease.
Conclusion In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5
Lday−1 to allow for the daily excretion of 2 to 3L of dilute (< 500mOsmkg−1) urine. Simple urinary markers of hydration
such as urine color or void frequency may be used to monitor and adjust intake.
Keywords Water· Renal· Metabolic· Arginine vasopressin· Copeptin
* Erica T. Perrier
erica.perrier@danone.com
1 Health, Hydration & Nutrition Science, Danone Research,
Route Départementale 128, 91767Palaiseaucedex, France
2 Department ofKinesiology, University ofConnecticut,
Storrs, CT, USA
3 Hydration & Nutrition, LLC, NewportNews, VA, USA
4 London Health Sciences Centre andWestern University,
London, ON, Canada
5 College ofHealth Solutions andHydration Science Lab,
Arizona State University, Phoenix, AZ, USA
6 Department ofPhysiology, Eberhard Karls University,
Tübingen, Germany
7 Westwood, MA, USA
8 Department ofClinical Sciences Malmö, Lund University,
Malmö, Sweden
9 Children’s Hospital Oakland Research Institute, Oakland,
CA, USA
10 Explorations Fonctionnelles Physiologiques, Hôpital
Rangueil, Toulouse, France
11 École de Kinésiologie et des Sciences de l’activité Physique,
Faculté de Médecine, Université de Montréal, Montréal, QC,
Canada
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1168 European Journal of Nutrition (2021) 60:1167–1180
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Introduction
Water is the largest constituent of the human body, repre-
senting roughly 40 to 62% of body mass [1]. Water bal-
ance is constantly challenged by transepidermal, respiratory,
fecal and urinary losses, with mean daily water turnover of
3.6 ± 1.2L day−1 [2] or 2.8 to 3.3 and 3.4 to 3.8Lday−1
in women, and men, respectively [3]. Only a small amount
of water is produced in the body (metabolic water, 0.25 to
0.35Lday−1 [2, 4]) and the human body has a limited capac-
ity to store water; so water losses must be replaced daily.
Thus, water has been called the ‘most essential’ nutrient
[5, 6].
The maintenance of body water balance is so critical for
survival that the volume of the body water pool is robustly
defended within a narrow range, even with large variabil-
ity in daily water intake. Evidence for this effective defense
is found in population studies [4], observations of habitual
low- vs. high-volume drinkers [7, 8], and water intake inter-
ventions [8–10], all of which demonstrate that large differ-
ences or changes in daily water intake do not appreciably
alter plasma osmolality, thereby substantiating the stability
of total body water volume. This tight regulation is governed
by sensitive osmotic sensing mechanisms which trigger two
key response elements: (1) the release of arginine vasopres-
sin (AVP), which acts via vasopressin V2 receptors (V2R)
on the renal collecting ducts, initiating renal water saving
when water intake is low; (2) the triggering of the sensation
of thirst to stimulate drinking.
Despite its importance, water is also referred to as a for-
gotten [11, 12], neglected, and under-researched [13] nutri-
ent. This is reflected by discrepancies between regional
water intake recommendations [4, 14], and the fact that
these reference values represent Adequate Intakes (AIs).
The AIs are based upon observed or experimentally derived
estimates of average water intake with insufficient scientific
evidence to establish a consumption target associated with
a health risk or benefit. In practice, from the perspective of
the general public, water may not even be visible in dietary
guidelines (e.g., www.choos emypl ate.gov). The implicit
message is that there is little or no need to pay attention to
water intake except in extreme situations; thirst is implicitly
assumed to be an adequate guide.
Hypothesis
This review advances the hypothesis that optimal water
intake positively impacts various aspects of health. We pro-
pose an evidence-based definition of optimal hydration as
a water intake sufficient to avoid excessive AVP secretion
and to ensure a generous excretion of dilute urine, sufficient
to avoid chronic or sustained renal water saving. For many,
this would imply drinking somewhat beyond physiological
thirst and likely more than the often-repeated target of ‘eight
glasses of water per day’ called into question by Valtin [15]
and others for lack of supporting evidence-based health
outcomes. Here, we review the existing evidence for two
specific mechanisms of action of how increased water intake
may impact health: (1) the direct effect of increased urine
flow on kidney and urinary tract health, and (2) the indirect
effect of lowering AVP concentration on kidney and meta-
bolic function. We conclude with a proposal for a range of
water intake that provides optimal hydration.
Literature review andsearch strategy
Searches for relevant literature were divided by subtopic.
Each subtopic was investigated by a group of two to three
authors and involved at least one expert with current, rele-
vant clinical practice or recent research activity. Search strat-
egy included PubMed and Google Scholar using relevant
keywords for each health outcome (e.g., for kidney stones:
kidney, stones, lithiasis, fluid, water, urine, flow, volume).
This was accompanied by manual search of article refer-
ence lists and the publication knowledge and expertise of
relevant practitioners for each area studied (e.g., nephrology,
physiology, metabolic health). For health outcomes included
in Tables1 and 2, only human studies (observational or
interventional) were included; animal or mechanistic work
is cited where relevant to describe or support a plausible
mechanism. No systematic assessment of study quality was
performed. The initial search included articles available
through the end of 2018; however, subsequent modifications
to the manuscript resulted in the inclusion of some more
recent references.
Direct eect ofincreased water intake
toincrease urine ow
While total body water and plasma osmolality are defended
within a narrow range, urine volume adjusts water losses
to compensate for fluctuations in daily water intake and
insensible losses. Urine output adjusts quickly to changes
in water intake, and 24-h urine volume is a reasonable sur-
rogate marker for high or low daily water intake in healthy
adults in free-living conditions [16]. Here, we review the
evidence for the importance of high urine flow in the second-
ary prevention of kidney stones and urinary tract infection.
A detailed description of individual studies is provided in
Table1.
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1169European Journal of Nutrition (2021) 60:1167–1180
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Kidney stones
Kidney stones are hard crystalline mineral deposits that form
inside the kidney or urinary tract. They occur in 10% of
the population worldwide [17] and recurrence is high: 40 to
60% of stone formers will relapse within 5years following a
first episode [18–20]. Stone formation results from dietary,
genetic and/or environmental factors. In particular, low fluid
intake and low urine volume have been shown to be signifi-
cant risk factors for kidney stones in first-time and recurrent
stone formers (Table1) [21–24]. Mechanistically, low urine
volume leads to higher concentrations of urinary solutes and
promotes urine supersaturation, favoring crystal nucleation
and stone growth [25]. Conversely, increased water intake
facilitates the flushing of crystals by increasing urine flow.
Table 1 Studies reporting a relationship between fluid intake and/or urinary hydration biomarkers and health outcomes related to urine dilution:
kidney stones and urinary tract infection
Empty cells denote that this variable was not reported
HPFS Health Professionals Follow-Up Study; NHS I Nurses’ Health Study; NHS II Nurses’ Health Study II; RCT Randomized Controlled Trial;
RR Relative risk; sd Standard Deviation; TFI Total Fluid Intake, volume of drinking water plus other beverages; UTI Urinary Tract Infection
Author (year)
Study type, cohort name, follow-up
period
Population
Fluid intake or urinary hydration marker associated with
health outcome
Health Outcome (Risk or Benefit)
Total fluid
intake volume
(TFI, L·day−1)
24-h urine volume (UVol, L·day−1) or
Urine osmolality (UOsm, mOsm·kg−1)
Borghi etal. (1996) [23]
Case–control
Recurrent stone formers
vs. healthy controls
UVol, Mean [sd]
Stone formers: 1.04 [0.24]
Controls: 1.35 [0.53]
Risk: Stone formers had lower spontane-
ous 24h urine volume than age, sex,
body weight, and socioeconomic-
matched controls
Borghi etal. (1996) [23]
RCT, 5-year follow-up
Recurrent stone formers
UVol, Mean [sd]
Intervention:
Pre: 1.1 [0.2]
Post: 2.6 [0.4]
Control:
Pre: 1.0 [0.2]
Post: 1.0 [0.2]
Benefit: Increasing urine volume reduced
kidney stone recurrence (12% vs. 27% in
control group), time between episodes,
and urine supersaturation in stone form-
ers
Curhan etal. (2004) [117]
Prospective, NHS II cohort, 8-year
follow-up
General population (women)
TFI, quintiles
Q1: ≤ 1.43
Q2: 1.43–1.85
Q3: 1.85–2.25
Q4: 2.25–2.77
Q5: ≥ 2.77
Benefit: Reduction in multivariate-adjusted
RR for incident kidney stones in women
in Q3, Q4, and Q5 (RR 0.79, 0.72, and
0.68, respectively), compared to refer-
ence (women with FI ≤ 1.43 L·day−1)
Curhan & Taylor (2008) [24]
Pooled retrospective study of 3 cohorts
(NHS I, NHS II, HPFS)
General population
UVol, Cutoff value
From 1.5 to ≥ 2.5 Benefit: Across three cohorts including
2,237 stone formers, individuals with a
urine volume ranging from 1.5L to more
than 2.5L·day−1 were shown to be at
lower risk of developing kidney stones
with corresponding RR ranging from
0.46 (urine volume 1.5 to 1.74L·day−1)
to 0.22 (urine volume ≥ 2,5 L·day−1),
compared to reference (urine vol-
ume ≤ 1.0L·day−1)
Curhan etal. (1993) [22]
Prospective cohort (HPFS), 4-year fol-
low up
General population (men)
TFI, quintiles
Q1: < 1.28
Q2: 1.28–1.67
Q3: 1.67–2.05
Q4: 2.05–2.54
Q5: ≥ 2.54
Benefit: Reduction in multivariate-adjusted
RR for incident kidney stones in men in
Q5 (RR = 0.71), compared to reference
(men with FI < 1.28 L·day−1)
Hooton etal. (2018) [42]
RCT, 12-month follow-up
Recurrent UTI (women)
TFI (interven-
tion group),
Mean [sd]
Pre: 1.1 [0.1]
Post: 2.8 [0.2]
UVol (intervention group), Mean [sd]
Pre: 0.9 [0.2]
Post: 2.2 [0.3]
UOsm (intervention group), Mean [sd]
Pre: 721 [169]
Post: 329 [117]
Benefit: 48% reduction in UTI recur-
rence in intervention group vs. control;
increased time between episodes; reduc-
tion in antibiotic use
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1170 European Journal of Nutrition (2021) 60:1167–1180
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In a 5-year randomized controlled trial (RCT), patients
were either instructed to increase water intake to achieve
a urine volume of 2Lday−1 without any further dietary
changes or were assigned to a control group receiving no
intervention [23]. Over the follow-up period, the recur-
rence of stones was lower (12%) in the intervention group,
who maintained a urine volume of more than 2.5Lday−1,
compared with the control group (27% recurrence) whose
urine volume remained at about 1.2Lday−1. Two systematic
reviews on this topic have concluded that high water intake
reduces long-term risk of kidney stone recurrence [26, 27].
In agreement with these findings, the European Association
of Urology and the American Urological Association cur-
rent guidelines for the secondary prevention of kidney stones
recommend stone-formers maintain a fluid intake that will
achieve a urine volume of at least 2.0 to 2.5Ldaily [28,
29]. Interestingly, increasing fluid intake also appears to be
perceived as one of the easiest lifestyle changes to make with
respect to stone recurrence. While dietary factors also influ-
ence stone formation, patients with recurrent kidney stones
reported being more confident in their ability to increase
fluid intake, compared to changing other dietary factors or
taking medicine [30].
In terms of primary prevention, we are only aware of one
study investigating the effects of increased habitual fluid
intake [31]. In an area of Israel with a high incidence of
urolithiasis, healthy inhabitants of one town participated in
an education program that encouraged adequate fluid intake,
while inhabitants of a second town did not participate in
the program. At the end of the 3-year study period, urine
output was found to be higher and incidence of urolithiasis
lower in the intervention group compared with the control
group. To date, no recommendation for primary stone pre-
vention has been proposed. However, considering the aggre-
gate of observational evidence, including a successful RCT
for secondary prevention, as well as a clear mechanism of
urine dilution to avoid supersaturation and stone formation,
increased water intake among low drinkers in general would
appear to be a reasonable, easy and cost-effective way to
reduce urolithiasis recurrence in known stone formers [32]
as well as in primary prevention [33].
Urinary tract infection
Urinary tract infections (UTI) are bacterial contaminations
of the genitourinary tract affecting a large part of the female
population and resulting in general discomfort and decreased
quality of life. Increased water intake is sometimes recom-
mended in clinical practice as a preventive strategy for UTI
in women suffering recurrent events. However, the empiri-
cal evidence for any relationship between UTI and water
intake or urinary markers of hydration is equivocal. Several
non-randomized studies reported that low intake of fluids or
reduced number of daily voids are associated with increased
risk of UTI [34–38]. In contrast, other published data show
no association between fluid intake and the risk of UTI, no
difference in fluid intake between women with recurrent
infections and healthy controls, and no effect of increased
water intake on UTI risk [39, 40]. A small crossover trial
published in 1995 demonstrated that self-assessment of
urine concentration encouraged lower urine osmolality and
reduced frequency of UTI [41]; however, the study had a
number of methodological problems including large number
of participants lost to follow-up, lack of a proper control
group, and not reporting fluid intake.
Recently, Hooton etal. published the first RCT assessing
the effect of increased water intake on the frequency of acute
uncomplicated lower UTI in premenopausal women [42].
One hundred and forty women suffering from recurrent UTI
with low fluid intake and low urine volume were randomly
assigned to increase their daily water intake by 1.5L or to
maintain their usual intake for 12months. Increasing water
intake (to 2.8Lday−1) and urine volume (to 2.2Lday−1)
resulted in a 48% reduction in UTI events. Of note, a sec-
ond benefit to increasing water intake was a reduction of
antibiotic use, for prophylaxis or treatment of UTI. The
proposed mechanism for the improvement in UTI recur-
rence was that increasing void frequency and urine volume
facilitated the flushing of bacteria and thus reduced bacterial
concentration in the urinary tract. More recently, a second
study of elderly patients in residential care homes found that
encouraging increased fluid intake by implementing struc-
tured ‘drink rounds’ multiple times per day reduced UTIs
requiring antibiotics by 58%, and UTIs requiring hospital
admission by 36% [43]. While the study did not measure
individual increases in fluid intake during the intervention,
the magnitude of reduction in UTI is substantial, and similar
to that reported by Hooton etal. in a younger population,
supporting the role for increased fluid intake in the second-
ary prevention of UTI.
Take home points
• Increasing fluid intake is effective in the secondary pre-
vention of kidney stones and urinary tract infection. Lit-
tle is known about whether high fluid intake is also effec-
tive in primary prevention.
• Mechanistically, increasing fluid intake results in lower
urine concentration and increased urine flow. The for-
mer may be important in preventing supersaturation and
crystal formation, while the latter encourages frequent
flushing of the urinary tract which may be helpful for
both kidney stone and UTI prevention.
• European and American urological associations encour-
age maintaining a fluid intake sufficient to produce 2 to
2.5L of urine per day to reduce risk of stone formation.
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1171European Journal of Nutrition (2021) 60:1167–1180
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Indirect eect ofincreased water intake:
mechanisms mediated byreducing
circulating AVP
AVP is a critical hormone for the regulation of body fluid
homeostasis. It can be secreted in response to small fluc-
tuations of serum osmolality and primarily regulates fluid
volume through its antidiuretic action on the kidney. Bind-
ing of AVP to the V2-receptors (V2R) located in the renal
collecting ducts, induces translocation of aquaporin-2 to the
cellular membrane and allowing increased water reabsorp-
tion [44] and the defense of total body water and plasma
osmolality. Copeptin, a stable C-terminal fragment of the
AVP precursor hormone released in a 1:1 ratio with AVP,
is a surrogate marker for AVP secretion [45]. The recent
availability of an ultra-sensitive assay for copeptin has dra-
matically increased research on AVP or copeptin and health
outcomes. Lower circulating copeptin is associated with
improved metabolic and renal outcomes (Table2).
AVP andmetabolic dysfunction
In addition to its well-defined role in concentrating urine and
regulating body water via the V2R, AVP also acts on other
AVP receptors (V1aR and V1bR) which occur in a variety of
central and peripheral tissues, with multiple and wide-rang-
ing physiological effects [46]. AVP may play an important
role in the development of metabolic disease because it stim-
ulates hepatic gluconeogenesis and glycogenolysis through
V1aR [47, 48] and triggers release of both glucagon and
insulin through V1bR in pancreatic islets [49]. Moreover,
AVP stimulates the release of adrenocorticotrophic hormone
(ACTH) via V1bR in the anterior pituitary gland, thereby
leading to elevated adrenal cortisol secretion and prompt-
ing undesirable cortisol-mediated gluconeogenesis [50, 51].
High plasma copeptin levels have been associated with
insulin resistance and metabolic syndrome in cross-sectional
population and community-based studies [52, 53]. Pooled
data from three large European cohorts also show that par-
ticipants in the top tertile of copeptin have higher fasting
plasma glucose compared to the bottom and medium ter-
tiles, and are more likely to have type 2 diabetes (T2DM)
[54]. Moreover, copeptin has been consistently identified
as an independent predictor of T2DM in four European
cohorts (Table2) [55–58], suggesting that AVP contributes
to the development of the disease. Furthermore, within dia-
betic patients, individuals with the highest copeptin level
had higher HbA1c levels [59], were more likely to develop
metabolic complications, heart disease, death and all-cause
mortality [60, 61].
A causal role for AVP in metabolic disorders is sup-
ported by preclinical evidence showing that high AVP
concentration impairs glucose regulation in rats, an effect
reversed by treatment with a selective V1aR antagonist
[62, 63]. In humans, causality is also supported by recent
evidence from a Mendelian randomization approach study
which reported that certain single nucleotide polymorphisms
within the AVP-neurophysin II gene were associated with
both higher AVP and higher incidence of impaired fasting
glucose in men, but not in women [56].
Individuals with lower habitual fluid intake have higher
AVP levels compared to those who consume more fluids,
despite similar plasma osmolality [7, 64], and increasing
plain water intake can lower AVP or copeptin over hours,
days, or weeks [10, 64, 65]. Compellingly, the most sub-
stantial reductions in copeptin appear to occur in those with
insufficient water intake as indicated by high baseline urine
osmolality, low urine volume and/or higher baseline copep-
tin level [65, 66]. Epidemiological evidence is inconsistent:
low water intake is linked with increased risk of new-onset
hyperglycemia [67], and an association between plain water
intake and elevated glycated hemoglobin has been noted in
men, but not women [68]. Pan etal. also found no asso-
ciation between plain water intake and incident T2DM in a
large cohort of women [69]. In the short-term, a six-week
pilot study in adults with high urine osmolality, low urine
volume, and high copeptin, demonstrated that increasing
water intake reduced circulating copeptin and resulted in
a small but significant reduction in fasting plasma glucose,
but no changes in fasting plasma insulin or glucagon [66].
However, a recent perspective paper pointed out that dif-
ferent manipulations to hydration have produced inconsist-
ent results, suggesting that the relationship between water
intake, hydration, AVP and metabolic response may be more
complex [70].
Overall, there is convergent epidemiological evidence
and a plausible mechanism for how higher circulating AVP
may contribute to increased risk for metabolic disease. There
is also evidence from short-term studies that in individuals
with higher AVP, increasing water intake can have an AVP-
lowering effect [10, 64, 65]. However, longer-term studies
are needed to demonstrate whether lowering AVP through
increased water intake is effective in maintaining metabolic
health.
Lower AVP andrenal water saving inchronic kidney
disease (CKD)
The rationale for use of water as a treatment in CKD is
based on its ability to suppress the secretion and thus the
detrimental effects of AVP on the kidneys [71, 72]. AVP
increases renal hyperfiltration and renal plasma flow with
its associated proteinuria, hypertension and renal scarring
[73, 74]. AVP antagonists reduce proteinuria, lower blood
pressure and prevent renal injury. Water intake acts as an
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1172 European Journal of Nutrition (2021) 60:1167–1180
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Table 2 Studies reporting a relationship between between fluid intake, urinary hydration markers, and/or copeptin, and health outcomes related to metabolic disease and kidney decline
Author (year)
Study type, cohort name, follow-up
period
Population
Fluid intake, urinary hydration biomarker or copeptin value associated with health outcome Health Outcome (Risk or Benefit)
Total water intake, total
fluid intake, or plain
water intake (L·day−1)
24-h urine volume (UVol,
L·day−1) or concentration
(UOsm, mOsm·kg−1 or
USG, unitless)
Plasma copeptin (pmol·L−1)
Abbasi etal. (2012) [57]
Prospective, PREVEND cohort,
7.7-year follow-up
General population
Median [25,75th percentile]
Men
Q4: 12.5 [10.5,15.5]
Women
Q3: 4.4 [4.0,4.9]
Q4: 7.6 [6.3,9.8]
Risk: Increased multivariate-adjusted odds of incident T2D in women, but not men, during
7.7year follow up, starting from the third quartile of baseline copeptin compared to Q1 (refer-
ence: 1.8 [1.4–2.1] pmol·L−1)
Risk: Increased odds of incident T2DM in men (more marginally significant, depending on adjust-
ment model) in the highest quartile of copeptin compared to Q1, 3.0 [2.3–3.5] pmol·L−1
Boertien etal. (2013) [118]
Prospective, ZODIAC-33, 6-year
follow up
T2DM
Quintiles
Q1 < 3.11
Q5 > 8.96
Risk: Highest quartile of copeptin had the most rapid rate of eGFR decline and largest change in
albumin:creatinine ratio compared to reference (Q1)
Clark etal. (2011) [79]
Prospective, Walkerton Health
Study Cohort, 6-year follow up
General population
UVol, quartiles
< 1.0
1–1.9
2–2.9
≥ 3.0
Risk: urine volume (< 1.0 L·day−1) more likely to demonstrate mild to moderate kidney function
decline, compared to reference (1–1.9 L·day−1), odds ratio multivariate adjusted
Benefit: High urine volume ≥ 3 L·day−1 less likely to demonstrate mild to moderate or severe kid-
ney function decline, compared to reference (1–1.9 L·day−1), odds ratios multivariate adjusted
El Boustany etal. (2018) [54]
Prospective, pooled analysis of 3
cohorts: DESIR, MDC-CC, PRE-
VEND, 8.5–16.5-year follow-up
General population
Tertiles, Median [IQR]
Men
T2: 5.9 [1.7]
T3: 10.6 [4.6]
Women:
T2: 3.5 [1.0]
T3: 6.5 [3.1]
Risk: Top tertile (T3): Higher fasting plasma glucose and triglycerides compared to T2, T1;
Risk: Top two tertiles (T2 and T3): kidney function decline compared to T1
Reference copeptin T1 3.2 [1.4], 2.1 [0.8] pmol·L−1 for men and women, respectively
Enhorning etal. (2010) [55]
Prospective, MDC-CC, 12-year
follow-up
General population
Median [25,75th percentile]
6.74 [4.44,10.9]
Risk: Baseline copeptin in participants developing T2DM during 12-year follow-up; compared to
4.90 [3.03–7.65] pmol·L−1 in those not developing T2DM (all participants NFG at baseline)
Enhorning etal. (2011) [52]
Cross-sectional, MDC-CC
General population
Men: ≥ 10.7 or Women: ≥ 6.47 Risk: Higher likelihood of hypertension, high CRP or abdominal obesity, multivariate-adjusted
Enhorning etal. (2011) [52]
Cross-sectional, MDC-CC
General population
Men: ≥ 4.61 or Women: ≥ 2.72 Risk: Higher likelihood of Metabolic Syndrome (age and sex adjusted only)
Enhorning etal. (2013) [119]
Prospective, MDC-CC, 15.8-year
follow up
General population
Median [25,75th percentile]
Men
Q3: 8.44 [7.64,9.53]
Q4: 13.5 [11.5,16.6]
Women
Q3: 5.14 [4.70,5.76]
Q4: 8.41 [7.22,10.45]
Risk: Third and fourth quartiles of copeptin: more likely to develop abdominal obesity, T2DM
(age- and sex-adjusted)
Risk: Fourth quartile of copeptin: More likely to develop metabolic syndrome (age and sex
adjusted); abdominal obesity, microalbuminuria (multivariate adjusted)
Enhorning etal. (2018) [66]
RCT, 6-week follow up
General population
TWI, Median [25,75th
percentile]
Pre: 1.9 [1.6,2.1]
Post: 2.7 [2.3,3.1]
UVol, Median [25,75th
percentile]
Pre: 1.06 [0.9,1.2]
Post: 2.27 [1.52,2.67]
UOsm, Median [25,75th
percentile]
Pre: 879 [705,996] Post:
384 [319,502]
Median [25,75th percentile]
Pre: 12.9 [7.4,21.9]
Post: 7.8 [4.6, 11.3]
Benefit: Increasing plain water intake by 0.9 L·day−1 resulted in a reduction in copeptin and was
accompanied by a lowering of fasting plasma glucose: from (mean [sd] 5.94 [0.44] to 5.74
[0.51] mmol·L−1 over a 6-week follow-up
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1173European Journal of Nutrition (2021) 60:1167–1180
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Empty cells denote that this variable was not reported
BRHS British Regional Heart Study; CRP C-reactive protein; DESIR Devenir des Spondylarthropathies Indifférenciées Récentes Cohort; DIABHYCAR Non-Insulin-Dependent Diabetes, Hyper-
tension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril Trial; MDC-CC Malmö Diet and Cancer Study, Cardiovascular Cohort; NFG Normal fasting glucose; NHANES
National Health and Nutrition Examination Survey; PREVEND Prevention of Renal and Vascular End-stage Disease Cohort; RCT Randomized controlled trial; RR Relative risk; SURDIAGENE
Survival Diabetes and Genetics Cohort; T2DM Type 2 diabetes mellitus; TFI Total Fluid Intake, volume of drinking water plus other beverages; TWI Total Water Intake, water coming from flu-
ids and food; ZODIAC-33 Zwolle Outpatient Diabetes project Integrating Available Care Cohort
Table 2 (continued)
Author (year)
Study type, cohort name, follow-up
period
Population
Fluid intake, urinary hydration biomarker or copeptin value associated with health outcome Health Outcome (Risk or Benefit)
Total water intake, total
fluid intake, or plain
water intake (L·day−1)
24-h urine volume (UVol,
L·day−1) or concentration
(UOsm, mOsm·kg−1 or
USG, unitless)
Plasma copeptin (pmol·L−1)
Meijer etal. (2010) [120]
Cross-sectional, PREVEND
General population
UVol, Mean by quintile
of copeptin (Q2-Q4
estimated from figure)
Men
Q1: 1.74
Q2: 1.60
Q3: 1.55
Q4: 1.45
Q5: 1.36
Women
Q1: 1.82
Q2: 1.70
Q3: 1.60
Q4: 1.55
Q5: 1.43
Quintiles:
Men
Q1: 0.6–3.7
Q2: 3.8–5.3
Q3: 5.4–7.3
Q4: 7.4–10.5
Q5: 10.5–632
Women
Q1: 0.1–2.1
Q2: 2.2–3.0
Q3: 3.1–4.2
Q4: 4.3–6.2
Q5: 6.3–131
Risk: Higher copeptin was associated with higher urinary albumin excretion, greater prevalence of
microalbuminuria, low urine volume and high urine osmolality in men and women, multivariate-
adjusted. Higher copeptin also significantly associated with lower eGFR (men and women), and
in men only, higher plasma glucose, prevalent T2DM, higher serum CRP, and higher serum
creatinine
Roussel etal. (2016) [56]
Prospective, DESIR cohort, 9-year
follow-up
General population
Quartiles
Q1: 0.91–2.92
Q2: 2.93–4.05
Q3: 4.06–6.57
Q4: 6.58–115
Benefit: Cumulated incident IFG or T2DM by quartile: 11, 14.5, 17.0, 23.5%, respectively in men
and women
Sontrop etal. (2013) [77]
Cross-sectional, NHANES
General population
Plain water intake,
Median of bottom 20%
0.5 L·day−1
Risk: More likely to have moderate CKD (multivariate-adjusted OR), compared to those with high
plain water intake (top 20%; median 2.6 L·day−1)
Strippoli etal. (2011) [76]
Cross-sectional, Blue Mountains,
Australia
General population
TFI, median of quintile
Q1: 1.8
Q5: 3.2
Benefit: Reduced risk of moderate CKD in the highest quintile compared to reference (Q1)
Velho etal. (2018) [121]
Prospective, pooled DIABHYCAR
and SURDIAGENE cohorts, 4.7-
year follow up
T2DM
Tertiles
median [IQR]
T3: 13.5 [6.5] and 16.2 [12.2] in both
cohorts, respectively
Risk: Highest tertile of copeptin had increased (multivariate-adjusted) risk of MI, coronary revas-
cularization, CHF, cardiovascular events, cardiovascular death, rapid kidney function decline,
doubling of serum creatinine or ESRD, over a median 4.7-year follow up, compared to the lowest
copeptin tertile (reference 3.7 [2.0] and 3.1 [1.9] pmol·L−1, respectively)
Wennamethee etal. (2015) [58]
Prospective, BRHS, 13-year
follow-up
General population (men
60–79years)
Quintiles
Q1: < 2.18
Q2: 2.18–3.12
Q3: 3.13–4.45
Q4: 4.46–6.78
Q5: ≥ 6.79
Risk: Higher incident T2DM in Q5 versus all other quintiles, multivariate-adjusted
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1174 European Journal of Nutrition (2021) 60:1167–1180
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AVP antagonist, as shown by the experimental animal work
of Bouby and Bankir in 1990 which demonstrated the thera-
peutic role of increased hydration in slowing progressive
loss of kidney function [72].
Water intake and its relationship with AVP in patients
with CKD is documented by various human observational
studies assessing hydration as a potential therapy in CKD.
However, there are inconsistencies in these studies regard-
ing the possible benefits of increased water intake to slow
and prevent CKD [75–79]. Briefly, cross-sectional studies
in Australian and American cohorts have reported a kidney
protective effect of higher fluid intake [76] and lower preva-
lence of CKD in participants reporting higher plain water
intake, a beneficial effect not observed for any other type
of beverage [77]. In contrast, a second prospective study
analyzing longitudinal data of the same Australian cohort
reported no significant association between total fluid intake
and longitudinal loss of kidney function [78]. This appar-
ent contradiction with the previous analysis may be due to
the fact that plain water intake, a major driver of high fluid
intake [80], was excluded from analysis. Finally, a 7-year
longitudinal study of over 2000 Canadians that controlled
for multiple baseline variables also demonstrated that higher
urine volumes significantly predicted slower renal decline
[79]. These observations are further strengthened by a longi-
tudinal study of more than 2000 CKD patients with 15-year
median follow-up demonstrating that those in the highest
quartile of fluid intake had better survival outcomes than
those in the lowest quartile [81].
To our knowledge there exists a single RCT on water
intake in CKD prevention. In a six-week pilot study of
29 patients with stage 3 CKD, Clark etal. showed that an
increased urine volume of 0.9L was associated with a sig-
nificant reduction in copeptin without any toxicity or meas-
urable change in quality of life [82, 83]. This pilot study led
to the Water Intake Trial [84], a parallel-group RCT in which
adults with stage 3 CKD and microalbuminuria were either
coached to increase water intake by 1 to 1.5Lday−1 above
their usual intake (high water intake (HWI) group), or to
maintain usual water intake. The primary analysis at 1-year
follow-up demonstrated that a 0.6-L increase in urine output
in the HWI group versus the control group was associated
with a small but significant reduction in copeptin, but not
associated with a difference in albuminuria nor in estimated
glomerular filtration rate (eGFR). However, this trial may
have focused on the wrong population, as the majority of
participants ingested approximately 2–3L of fluid per day
at baseline; consequently, the margin for improved hydra-
tion was small. Future RCTs should consider focusing on
the role of increased hydration in low water drinkers with
high copeptin levels and thus higher potential to respond to
increased water intake, include more precise measures of
renal function and possibly a longer follow-up.
Autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is
a genetic disorder characterized by development and enlarge-
ment of multiple cysts in the kidney, leading to loss of renal
function, hypertension, and renal failure in 50% of patients
by the age of 60 [85]. The major sites of cyst development in
ADPKD are the collecting ducts and distal nephrons, where
cyclic adenosine monophosphate (cAMP) stimulates both
epithelial cell proliferation and fluid secretion [86]. Since
AVP is a strong activator of cAMP in these loci [87, 88],
the rate of progression of the disease is associated with its
circulating concentration: a loss of urinary concentrating
ability early in ADPKD is associated with a concomitant
rise in AVP [89–93]. Further, preclinical studies demonstrate
that ADPKD progression is slower in animals lacking AVP,
and that in AVP knock-out animal models, desmopressin,
a synthetic AVP analogue, accelerates disease progression
[87, 94].
Reducing AVP action represents a recent therapeutic
target for patients with ADPKD, with two possible mecha-
nisms: (1) blocking its receptors; more specifically the V2R
in the collecting ducts; or (2) decreasing circulating AVP.
Administration of vaptans, a class of nonpeptide AVP recep-
tor antagonists, in particular tolvaptan, an oral selective
antagonist of the V2R, decrease cAMP in epithelial cells of
the collecting ducts and distal nephron [95]. A recent RCT
reported inhibition of the action of AVP by tolvaptan signifi-
cantly slows the rate of disease progression [96].
The suppression of AVP by increasing water intake could
also slow renal cyst growth in ADPKD [87, 88, 94, 96, 97].
Rodent models of polycystic kidney disease have shown
AVP suppression by increased water intake is associated
with a significant renal-protective effect [87]. However, data
available in humans are limited and conflicting. A positive
effect of high water intake on ADPKD was observed in one
post hoc analysis [98] and two short-term interventional tri-
als [98, 99] while a negative effect of high water intake was
reported in a small observational cohort study [100] One
large RCT is currently underway to determine the efficacy
and safety of increasing water intake to prevent the progres-
sion of ADPKD over a 3-year period [101].
Take home points
• AVP, or the antidiuretic hormone, is most well-known for
its central role in maintaining body water balance. How-
ever, AVP can also stimulate hepatic gluconeogenesis
and glycogenolysis and can moderate glucose-regulating
and corticotrophic hormones through its V1a and V1b
receptors. The AVP-V2 receptor is also implicated in the
pathophysiology of a particular form of kidney disease
(ADPKD).
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1175European Journal of Nutrition (2021) 60:1167–1180
1 3
• In epidemiological studies, higher circulating AVP,
measured by its equimolar surrogate, copeptin, is asso-
ciated both cross-sectionally and longitudinally with
higher odds for kidney function decline, components of
the metabolic syndrome, and incident T2DM.
• Short-term intervention studies suggest that in individu-
als with higher AVP, increasing water intake can have
an AVP-lowering effect. However, it is unclear whether
lowering AVP through increased water intake will reduce
disease risk.
Optimal hydration
If water intake may contribute to maintaining kidney and
metabolic health, what would constitute optimal hydration
and how much water should one consume?
Based on the evidence above, optimal hydration should
result in excretion of a generous volume of dilute urine, suf-
ficient to avoid chronic or sustained renal water saving and
excess AVP secretion. Individual needs vary; nonetheless,
the available data (Tables1, 2) provide a starting point for
practical and evidence-based recommendations.
The first recommendation is that beyond replacing daily
fluid losses, optimal hydration should be viewed as allow-
ing the excretion of a sufficient urine volume to avoid urine
concentration and supersaturation. Based on the evidence
for fluid intake, urine volume, and kidney stones and UTI, it
would appear reasonable to maintain a volume of excreted
urine of 2 to 3L per day. To account for other avenues of
water loss (insensible, fecal [4, 14]), achieving a urine vol-
ume of 2 to 3L would require consuming a fluid volume
slightly higher than the AIs currently proposed by EFSA
[14], and approaching the IOM AIs [4]. We suggest that
daily total water intake for healthy adults in a temperate cli-
mate, performing, at most, mild to moderate physical activ-
ity should be 2.5 to 3.5Lday−1. While total water intake
includes water from both food and fluids, plain water is the
only fluid the body needs. Plain water and other healthy bev-
erages should make up the bulk of daily intake. A practical,
evidence-based scoring tool for evaluating healthy beverage
choices has been proposed by Duffey etal. [102].
The second recommendation, for healthy individuals
as well as in those with metabolic dysfunction, is to drink
enough to reduce excessive AVP secretion as this may be
beneficial for the kidney and reduce metabolic risk. This
is especially relevant for individuals who may be under-
hydrated [103], with low 24h urine volume or high urine
concentration suggestive of AVP secretion linked to insuf-
ficient water intake. While higher circulating AVP is asso-
ciated with increased disease risk, to date there is insuf-
ficient data to suggest a level of copeptin which may be
appropriate to target for risk reduction. However, the use
of urinary biomarkers of hydration such as osmolality can
provide useful information reflecting urine concentrating
and diluting mechanisms and overall antidiuretic activity.
Multiple authors have proposed cut-offs representing de- or
hypohydration for several urinary and plasma biomarkers
(Fig.1), conversely, suggestions for optimal hydration are
infrequently provided [28, 104–116]. Several years ago a
cutoff of 500mOsmkg−1 was proposed as a reasonable
target for optimal hydration, based on retrospective analy-
ses of existing data [109] indicating that this cut-off would
represent sufficient water intake to produce adequate urine
Fig. 1 Terminology and associated cut-off values for common bio-
markers of hydration.*Defined as ‘impending dehydration’. †In the
original text, these values are described as limits for euhydration
(e.g., POsm < 290, UOsm < 700). For clarity we have positioned these
values as limits for dehydration (e.g., POsm ≥ 290, UOsm ≥ 700)
in order to avoid the interpretation that these values were limits for
insufficient hydration. ‡Decision level for 95% probability of dehy-
dration. §Approximate range of plasma copeptin in bottom quartile
or other reference interval (lowest risk for kidney or cardiometabolic
disease)—see Table 2. ||Approximate range of plasma copeptin for
increased risk for kidney or cardiometabolic disease—see Table2
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1176 European Journal of Nutrition (2021) 60:1167–1180
1 3
volume with respect to kidney health risk, and reduce anti-
diuretic effort and circulating AVP. Today, several RCTs
have demonstrated that lowering 24h urine osmolality to
approach 500mOsmkg−1 or below can reduce circulating
copeptin [10, 64, 65] as well as improve metabolic markers
[66] and reduce UTI incidence [42]. For clinician or home
use, maintaining a urine specific gravity of less than 1.013,
or a urine color of 3 or below [108] on an eight-point color
scale [107], or a 24h void frequency of at least 5 to 7 voids
daily [114, 115] are suggestive of a fluid intake sufficient
to achieve optimal hydration (Fig.1). As color and void
frequency are accessible without specific laboratory instru-
ments, they may be used by the general population for daily
hydration awareness.
Author contributions All authors were involved in the research design
(project conception, development of overall research and review plan)
and contributed substantially to the drafting and critical revision of the
manuscript. ETP and FP had primary responsibility for final content;
all authors had access to the references used in the preparation of this
review and have read and approved the final manuscript.
Funding No funding was provided for the completion of this review.
Compliance with ethical standards
Conflict of interest ETP, JHB, AD, IG, AI, CM, IS, TV and MV are or
were employed by Danone Research during the writing of this review.
LEA, WCC, SAK, FL, HRL, OM, JDS, IT and FP have previously
received consulting honoraria and/or research grants from Danone Re-
search. No financial compensation was provided for the conception,
drafting or critical revision of this manuscript.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
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References
1. Perrier ET, Armstrong LE, Daudon M, Kavouras S, Lafontan M,
Lang F, Peronnet F, Stookey JD, Tack I, Klein A (2014) From
state to process: defining hydration. Obes Facts 7(Suppl 2):6–12.
https ://doi.org/10.1159/00036 0611
2. Johnson EC, Peronnet F, Jansen LT, Capitan-Jimenez C, Adams
JD, Guelinckx I, Jimenez L, Mauromoustakos A, Kavouras SA
(2017) Validation testing demonstrates efficacy of a 7-day fluid
record to estimate daily water intake in adult men and women
when compared with total body water turnover measurement. J
Nutr 147(10):2001–2007. https ://doi.org/10.3945/jn.117.25337
7
3. Raman A, Schoeller DA, Subar AF, Troiano RP, Schatzkin A,
Harris T, Bauer D, Bingham SA, Everhart JE, Newman AB,
Tylavsky FA (2004) Water turnover in 458 American adults
40–79 yr of age. Am J Physiol Renal Physiol 286(2):F394–F401
4. Institute of Medicine (IOM) (2004) Dietary reference intakes for
water, potassium, sodium, chloride, and sulfate. National Acad-
emies Press, Washington, DC
5. Manz F, Wentz A, Sichert-Hellert W (2002) The most essen-
tial nutrient: defining the adequate intake of water. J Pediatr
141(4):587–592
6. Jequier E, Constant F (2010) Water as an essential nutrient: the
physiological basis of hydration. Eur J Clin Nutr 64(2):115–123
7. Perrier E, Vergne S, Klein A, Poupin M, Rondeau P, Le Bellego
L, Armstrong LE, Lang F, Stookey J, Tack I (2013) Hydration
biomarkers in free-living adults with different levels of habitual
fluid consumption. Br J Nutr 109(9):1678–1687. https ://doi.
org/10.1017/S0007 11451 20036 01
8. Johnson EC, Munoz CX, Le Bellego L, Klein A, Casa DJ,
Maresh CM, Armstrong LE (2015) Markers of the hydration
process during fluid volume modification in women with habitual
high or low daily fluid intakes. Eur J Appl Physiol 115(5):1067–
1074. https ://doi.org/10.1007/s0042 1-014-3088-2
9. Perrier E, Demazieres A, Girard N, Pross N, Osbild D, Metzger
D, Guelinckx I, Klein A (2013) Circadian variation and respon-
siveness of hydration biomarkers to changes in daily water intake.
Eur J Appl Physiol 113(8):2143–2151. https ://doi.org/10.1007/
s0042 1-013-2649-0
10. Lemetais G, Melander O, Vecchio M, Bottin JH, Enhorning S,
Perrier ET (2018) Effect of increased water intake on plasma
copeptin in healthy adults. Eur J Nutr 57(5):1883–1890. https ://
doi.org/10.1007/s0039 4-017-1471-6
11. Hauff K (1991) Water: the forgotten nutrient. AGRIS 13(5):11–16
12. Wertli M, Suter PM (2006) Water—the forgotten nutri-
ent. Praxis (Bern 1994) 95(39):1489–1495. https ://doi.
org/10.1024/1661-8157.95.39.1489
13. Rush EC (2013) Water: neglected, unappreciated and under
researched. Eur J Clin Nutr 67:492–495
14. EFSA (2010) Scientific opinion on dietary reference values for
water. EFSA Journal 8(3):1459–1506
15. Valtin H (2002) "Drink at least eight glasses of water a day."
Really? Is there scientific evidence for “8 x 8”? Am J Physiol
Regul Integr Comp Physiol 283(5):R993–1004. https ://doi.
org/10.1152/ajpre gu.00365 .2002
16. Perrier E, Rondeau P, Poupin M, Le Bellego L, Armstrong LE,
Lang F, Stookey J, Tack I, Vergne S, Klein A (2013) Relation
between urinary hydration biomarkers and total fluid intake in
healthy adults. Eur J Clin Nutr 67(9):939–943
17. Brenner B, Rector J (2008) Nephrolithiasis in Brenner and Rec-
tor’s: The Kidney, 8th edn. Elsevier Saunders, Philadelphia
18. Ettinger B (1979) Recurrence of nephrolithiasis. A six-year pro-
spective study. Am J Med 67(2):245–248
19. Hosking DH, Erickson SB, Van den Berg CJ, Wilson DM, Smith
LH (1983) The stone clinic effect in patients with idiopathic cal-
cium urolithiasis. J Urol 130(6):1115–1118
20. Sutherland JW, Parks JH, Coe FL (1985) Recurrence after a sin-
gle renal stone in a community practice. Miner Electrol Metab
11(4):267–269
21. Robertson WG, Peacock M, Heyburn PJ, Marshall DH, Clark PB
(1978) Risk factors in calcium stone disease of the urinary tract.
Br J Urol 50(7):449–454
22. Curhan GC, Willett WC, Rimm EB, Stampfer MJ (1993) A pro-
spective study of dietary calcium and other nutrients and the risk
of symptomatic kidney stones. N Engl J Med 328(12):833–838.
https ://doi.org/10.1056/nejm1 99303 25328 1203
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1177European Journal of Nutrition (2021) 60:1167–1180
1 3
23. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini
A (1996) Urinary volume, water and recurrences in idiopathic
calcium nephrolithiasis: a 5-year randomized prospective study.
J Urol 155(3):839–843
24. Curhan GC, Taylor EN (2008) 24-h uric acid excretion and the
risk of kidney stones. Kidney Int 73(4):489–496. https ://doi.
org/10.1038/sj.ki.50027 08
25. Ratkalkar VN, Kleinman JG (2011) Mechanisms of stone forma-
tion. Clin Rev Bone Miner Metab 9(3–4):187–197. https ://doi.
org/10.1007/s1201 8-011-9104-8
26. Fink HA, Akornor JW, Garimella PS, MacDonald R, Cutting A,
Rutks IR, Monga M, Wilt TJ (2009) Diet, fluid, or supplements
for secondary prevention of nephrolithiasis: a systematic review
and meta-analysis of randomized trials. Eur Urol 56(1):72–80.
https ://doi.org/10.1016/j.eurur o.2009.03.031
27. Xu C, Zhang C, Wang XL, Liu TZ, Zeng XT, Li S, Duan XW
(2015) Self-fluid management in prevention of kidney stones: a
PRISMA-compliant systematic review and dose-response meta-
analysis of observational studies. Medicine 94(27):e1042. https
://doi.org/10.1097/md.00000 00000 00104 2
28. Türk C, Knoll T, Petrik A, Sarica K, Straub CM, Seitz C (2011)
Guidelines on Urolithiasis. European Association of Urology.
https ://urowe b.org/wp-conte nt/uploa ds/20-Uroli thias is.pdf
29. Pearle MS, Goldfarb DS, Assimos DG, Curhan GC, Denu-Giocca
CJ, Matlaga BR, Turk MT, White JR (2014) Medical manage-
ment of kidney stones: AUA Guideline. American Urological
Association (AUA) Guideline, https ://www.auane t.org/docum
ents/educa tion/clini cal-guida nce/Medic al-Manag ement -of-Kidne
y-Stone s.pdf
30. McCauley LR, Dyer AJ, Stern K, Hicks T, Nguyen MM (2012)
Factors influencing fluid intake behavior among kidney stone
formers. J Urol 187(4):1282–1286. https ://doi.org/10.1016/j.
juro.2011.11.111
31. Frank M, De VA (1966) Prevention of urolithiasis. Education to
adequate fluid intake in a new town situated in the Judean Desert
Mountains. Arch Environ Health 13(5):625–630
32. Lotan Y, Jimenez IB, Lenoir-Wijnkoop I, Daudon M, Molinier L,
Tack I, Nuijten MJ (2012) Increased water intake as a prevention
strategy for recurrent urolithiasis: major impact of compliance
on cost-effectiveness. J Urol 12:10
33. Lotan Y, Pearle MS (2011) Cost-effectiveness of primary preven-
tion strategies for nephrolithiasis. J Urol 186(2):550–555. https
://doi.org/10.1016/j.juro.2011.03.133
34. Adatto K, Doebele KG, Galland L, Granowetter L (1979)
Behavioral factors and urinary tract infection. JAMA
241(23):2525–2526
35. Ervin C, Komaroff AL, Pass TM (1980) Behavioral factors and
urinary tract infection. JAMA 243(4):330–331
36. Pitt M (1989) Fluid intake and urinary tract infection. Nurs Times
85(1):36–38
37. Su SB, Wang JN, Lu CW (2002) Guo HR (2006) Reducing
urinary tract infections among female clean room workers.
J Women’s Health 15(7):870–876. https ://doi.org/10.1089/
jwh.2006.15.870
38. Vyas S, Varshney D, Sharma P, Juyal R, Nautiyal V, Shrotriya
V (2015) An overview of the predictors of symptomatic urinary
tract infection among nursing students. Ann Med Health Sci Res
5(1):54–58. https ://doi.org/10.4103/2141-9248.14979 0
39. Remis RS, Gurwith MJ, Gurwith D, Hargrett-Bean NT, Layde
PM (1987) Risk factors for urinary tract infection. Am J Epide-
miol 126(4):685–694
40. Robinson SB, Rosher RB (2002) Can a beverage cart help
improve hydration? Geriatr Nurs 23(4):208–211
41. Eckford SD, Keane DP, Lamond E, Jackson SR, Abrams P (1995)
Hydration monitoring in the prevention of recurrent idiopathic
urinary tract infections in premenopausal women. Br J Urol
76:90–93
42. Hooton TM, Vecchio M, Iroz A, Tack I, Dornic Q, Seksek I,
Lotan Y (2018) Effect of increased daily water intake in pre-
menopausal women with recurrent urinary tract infections: a ran-
domized clinical trial. JAMA Intern Med 178(11):1509–1515.
https ://doi.org/10.1001/jamai ntern med.2018.4204
43. Lean K, Nawaz RF, Jawad S, Vincent C (2019) Reducing urinary
tract infections in care homes by improving hydration. BMJ Open
Qual 8(3):e000563–e000563. https ://doi.org/10.1136/bmjoq
-2018-00056 3
44. Bankir L (2001) Antidiuretic action of vasopressin: quantitative
aspects and interaction between V1a and V2 receptor-mediated
effects. Cardiovasc Res 51(3):372–390
45. Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Assay
for the measurement of copeptin, a stable peptide derived from
the precursor of vasopressin. Clin Chem 52(1):112–119
46. Mavani GP, DeVita MV, Michelis MF (2015) A review of the
nonpressor and nonantidiuretic actions of the hormone vasopres-
sin. Front Med 2:19. https ://doi.org/10.3389/fmed.2015.00019
47. Whitton PD, Rodrigues LM, Hems DA (1978) Stimulation by
vasopressin, angiotensin and oxytocin of gluconeogenesis in
hepatocyte suspensions. Biochem J 176(3):893–898
48. Keppens S, de Wulf H (1979) The nature of the hepatic recep-
tors involved in vasopressin-induced glycogenolysis. Biochem
Biophys Acta 588(1):63–69
49. Abu-Basha EA, Yibchok-Anun S, Hsu WH (2002) Glucose
dependency of arginine vasopressin-induced insulin and
glucagon release from the perfused rat pancreas. Metabolism
51(9):1184–1190
50. Rizza RA, Mandarino LJ, Gerich JE (1982) Cortisol-induced
insulin resistance in man: impaired suppression of glucose pro-
duction and stimulation of glucose utilization due to a postrecep-
tor detect of insulin action. J Clin Endocrinol Metab 54(1):131–
138. https ://doi.org/10.1210/jcem-54-1-131
51. Tanoue A, Ito S, Honda K, Oshikawa S, Kitagawa Y, Koshimizu
TA, Mori T, Tsujimoto G (2004) The vasopressin V1b recep-
tor critically regulates hypothalamic-pituitary-adrenal axis
activity under both stress and resting conditions. J Clin Invest
113(2):302–309. https ://doi.org/10.1172/jci19 656
52. Enhorning S, Struck J, Wirfalt E, Hedblad B, Morgenthaler NG,
Melander O (2011) Plasma copeptin, a unifying factor behind the
metabolic syndrome. J Clin Endocrinol Metab 96(7):1065–1072.
https ://doi.org/10.1210/jc.2010-2981
53. Saleem U, Khaleghi M, Morgenthaler NG, Bergmann A, Struck
J, Mosley TH Jr, Kullo IJ (2009) Plasma carboxy-terminal pro-
vasopressin (copeptin): a novel marker of insulin resistance and
metabolic syndrome. J Clin Endocrinol Metab 94(7):2558–2564.
https ://doi.org/10.1210/jc.2008-2278
54. El Boustany R, Tasevska I, Meijer E, Kieneker LM, Enhorning
S, Lefevre G, Mohammedi K, Marre M, Fumeron F, Balkau B,
Bouby N, Bankir L, Bakker SJ, Roussel R, Melander O, Gan-
sevoort RT, Velho G (2018) Plasma copeptin and chronic kidney
disease risk in 3 European cohorts from the general population.
JCI Insight. https ://doi.org/10.1172/jci.insig ht.12147 9
55. Enhorning S, Wang TJ, Nilsson PM, Almgren P, Hedblad B,
Berglund G, Struck J, Morgenthaler NG, Bergmann A, Lindholm
E, Groop L, Lyssenko V, Orho-Melander M, Newton-Cheh C,
Melander O (2010) Plasma copeptin and the risk of diabetes mel-
litus. Circulation 121(19):2102–2108. https ://doi.org/10.1161/
CIRCU LATIO NAHA.109.90966 3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1178 European Journal of Nutrition (2021) 60:1167–1180
1 3
56. Roussel R, El Boustany R, Bouby N, Potier L, Fumeron F,
Mohammedi K, Balkau B, Tichet J, Bankir L, Marre M, Velho
G (2016) Plasma copeptin, AVP gene variants, and incidence
of type 2 diabetes in a cohort from the community. J Clin
Endocrinol Metab 101(6):2432–2439. https ://doi.org/10.1210/
jc.2016-1113
57. Abbasi A, Corpeleijn E, Meijer E, Postmus D, Gansevoort RT,
Gans RO, Struck J, Hillege HL, Stolk RP, Navis G, Bakker SJ
(2012) Sex differences in the association between plasma copep-
tin and incident type 2 diabetes: the Prevention of Renal and
Vascular Endstage Disease (PREVEND) study. Diabetologia
55(7):1963–1970. https ://doi.org/10.1007/s0012 5-012-2545-x
58. Wannamethee SG, Welsh P, Papacosta O, Lennon L, Whin-
cup PH, Sattar N (2015) Copeptin, insulin resistance, and risk
of incident diabetes in older men. J Clin Endocrinol Metab
100(9):3332–3339. https ://doi.org/10.1210/jc.2015-2362
59. Velho G, Bouby N, Hadjadj S, Matallah N, Mohammedi K, Fum-
eron F, Potier L, Bellili-Munoz N, Taveau C, Alhenc-Gelas F,
Bankir L, Marre M, Roussel R (2013) Plasma copeptin and renal
outcomes in patients with type 2 diabetes and albuminuria. Dia-
betes Care 36(11):3639–3645. https ://doi.org/10.2337/dc13-0683
60. Riphagen IJ, Boertien WE, Alkhalaf A, Kleefstra N, Gansevoort
RT, Groenier KH, van Hateren KJ, Struck J, Navis G, Bilo HJ,
Bakker SJ (2013) Copeptin, a surrogate marker for arginine vaso-
pressin, is associated with cardiovascular and all-cause mortality
in patients with type 2 diabetes (ZODIAC-31). Diabetes Care
36(10):3201–3207. https ://doi.org/10.2337/dc12-2165
61. Enhorning S, Hedblad B, Nilsson PM, Engstrom G, Melander
O (2015) Copeptin is an independent predictor of diabetic heart
disease and death. Am Heart J 169(4):549–556. https ://doi.
org/10.1016/j.ahj.2014.11.020
62. Taveau C, Chollet C, Waeckel L, Desposito D, Bichet DG, Arthus
MF, Magnan C, Philippe E, Paradis V, Foufelle F, Hainault I,
Enhorning S, Velho G, Roussel R, Bankir L, Melander O, Bouby
N (2015) Vasopressin and hydration play a major role in the
development of glucose intolerance and hepatic steatosis in obese
rats. Diabetologia 58(5):1081–1090. https ://doi.org/10.1007/
s0012 5-015-3496-9
63. Taveau C, Chollet C, Bichet DG, Velho G, Guillon G, Corbani
M, Roussel R, Bankir L, Melander O, Bouby N (2017) Acute
and chronic hyperglycemic effects of vasopressin in normal rats:
involvement of V1A receptors. Am J Physiol Endocrinol Metab
312(3):E127–E135. https ://doi.org/10.1152/ajpen do.00269 .2016
64. Johnson EC, Munoz CX, Jimenez L, Le Bellego L, Kupchak
BR, Kraemer WJ, Casa DJ, Maresh CM, Armstrong LE (2016)
Hormonal and thirst modulated maintenance of fluid balance in
young women with different levels of habitual fluid consumption.
Nutrients. https ://doi.org/10.3390/nu805 0302
65. Enhorning S, Tasevska I, Roussel R, Bouby N, Persson M, Burri
P, Bankir L, Melander O (2017) Effects of hydration on plasma
copeptin, glycemia and gluco-regulatory hormones: a water
intervention in humans. Eur J Nutr 58(1):315–324. https ://doi.
org/10.1007/s0039 4-017-1595-8
66. Enhorning S, Brunkwall L, Tasevska I, Ericson U, Tholin JP,
Persson M, Lemetais G, Vanhaecke T, Dolci A, Perrier ET, Mel-
ander O (2018) Water supplementation reduces copeptin and
plasma glucose in adults with high copeptin: the H2O metabo-
lism pilot study. J Clin Endocrinol Metab 104(6):1917–1925.
https ://doi.org/10.1210/jc.2018-02195
67. Roussel R, Fezeu L, Bouby N, Balkau B, Lantieri O, Alhenc-
Gelas F, Marre M, Bankir L (2011) Low water intake and risk
for new-onset hyperglycemia. Diabetes Care 34(12):2551–2554.
https ://doi.org/10.2337/dc11-0652
68. Carroll HA, Betts JA, Johnson L (2016) An investigation into
the relationship between plain water intake and glycated Hb
(HbA1c): a sex-stratified, cross-sectional analysis of the UK
National Diet and Nutrition Survey (2008–2012). Br J Nutr
116(10):1770–1780. https ://doi.org/10.1017/s0007 11451 60036
88
69. Pan A, Malik VS, Schulze MB, Manson JE, Willett WC, Hu FB
(2012) Plain-water intake and risk of type 2 diabetes in young
and middle-aged women. Am J Clin Nutr 95(6):1454–1460. https
://doi.org/10.3945/ajcn.111.03269 8
70. Carroll HA, James LJ (2019) Hydration, arginine vasopressin,
and glucoregulatory health in humans: a critical perspective.
Nutrients. https ://doi.org/10.3390/nu110 61201
71. Bardoux P, Bichet DG, Martin H, Gallois Y, Marre M, Arthus
MF, Lonergan M, Ruel N, Bouby N, Bankir L (2003) Vasopres-
sin increases urinary albumin excretion in rats and humans:
involvement of V2 receptors and the renin-angiotensin system.
Nephrol Dial Transplant 18(3):497–506
72. Bouby N, Bachmann S, Bichet D, Bankir L (1990) Effect of
water intake on the progression of chronic renal failure in the 5/6
nephrectomized rat. Am J Physiol 258(4 Pt 2):F973–979. https ://
doi.org/10.1152/ajpre nal.1990.258.4.F973
73. Bardoux P, Martin H, Ahloulay M, Schmitt F, Bouby N, Trinh-
Trang-Tan MM, Bankir L (1999) Vasopressin contributes to
hyperfiltration, albuminuria, and renal hypertrophy in diabetes
mellitus: study in vasopressin-deficient Brattleboro rats. Proc
Natl Acad Sci U S A 96(18):10397–10402
74. Bolignano D, Zoccali C (2010) Vasopressin beyond water:
implications for renal diseases. Curr Opin Nephrol Hypertens
19(5):499–504. https ://doi.org/10.1097/MNH.0b013 e3283 3d35c
f
75. Hebert LA, Greene T, Levey A, Falkenhain ME, Klahr S (2003)
High urine volume and low urine osmolality are risk fac-
tors for faster progression of renal disease. Am J Kidney Dis
41(5):962–971
76. Strippoli GF, Craig JC, Rochtchina E, Flood VM, Wang JJ,
Mitchell P (2011) Fluid and nutrient intake and risk of chronic
kidney disease. Nephrology 16(3):326–334
77. Sontrop JM, Dixon SN, Garg AX, Buendia-Jimenez I, Dohein O,
Huang SH, Clark WF (2013) Association between water intake,
chronic kidney disease, and cardiovascular disease: a cross-sec-
tional analysis of NHANES data. Am J Nephrol 37(5):434–442
78. Palmer SC, Wong G, Iff S, Yang J, Jayaswal V, Craig JC,
Rochtchina E, Mitchell P, Wang JJ, Strippoli GF (2014) Fluid
intake and all-cause mortality, cardiovascular mortality and
kidney function: a population-based longitudinal cohort study.
Nephrol Dial Transpl 29(7):1377–1384. https ://doi.org/10.1093/
ndt/gft50 7
79. Clark WF, Sontrop JM, Macnab JJ, Suri RS, Moist L, Salva-
dori M, Garg AX (2011) Urine volume and change in estimated
GFR in a community-based cohort study. Clin J Am Soc Nephrol
6(11):2634–2641
80. Perrier E, Klein A, Guelinckx I (2014) Water from fluids is the
main driver of total water intake in healthy French adults. In:
Paper presented at the 38th National Nutrient Databank Con-
ference. https ://www.nutri entda tacon f.org/PastC onf/NDBC3 8/
NNDC3 8_Poste rAbst racts .pdf
81. Wu LW, Chen WL, Liaw FY, Sun YS, Yang HF, Wang CC,
Lin CM, Tsao YT (2016) Association between fluid intake and
kidney function, and survival outcomes analysis: a nationwide
population-based study. BMJ Open 6(5):e010708. https ://doi.
org/10.1136/bmjop en-2015-01070 8
82. Clark WF, Sontrop JM, Huang SH, Gallo K, Moist L, House AA,
Weir MA, Garg AX (2013) The chronic kidney disease Water
Intake Trial (WIT): results from the pilot randomised controlled
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1179European Journal of Nutrition (2021) 60:1167–1180
1 3
trial. BMJ Open 3(12):e003666. https ://doi.org/10.1136/bmjop
en-2013-00366 6
83. Sontrop JM, Huang SH, Garg AX, Moist L, House AA, Gallo
K, Clark WF (2015) Effect of increased water intake on plasma
copeptin in patients with chronic kidney disease: results from
a pilot randomised controlled trial. BMJ Open 5(11):e008634.
https ://doi.org/10.1136/bmjop en-2015-00863 4
84. Clark WF, Sontrop JM, Huang SH, Gallo K, Moist L, House AA,
Cuerden MS, Weir MA, Bagga A, Brimble S, Burke A, Muirhead
N, Pandeya S, Garg AX (2018) Effect of coaching to increase
water intake on kidney function decline in adults with chronic
kidney disease: The CKD WIT randomized clinical trial. JAMA
319(18):1870–1879. https ://doi.org/10.1001/jama.2018.4930
85. Chebib FT, Torres VE (2016) Autosomal dominant polycys-
tic kidney disease: core curriculum 2016. Am J Kidney Dis
67(5):792–810. https ://doi.org/10.1053/j.ajkd.2015.07.037
86. Grantham JJ (2003) Lillian Jean Kaplan International Prize for
advancement in the understanding of polycystic kidney disease.
Understanding polycystic kidney disease: a systems biology
approach. Kidney Int 64(4):1157–1162
87. Wang X, Wu Y, Ward C, Harris P, Torres V (2008) Vasopressin
directly regulates cyst growth in polycystic kidney disease. J Am
Soc Nephrol 19:102–108
88. Gattone V, Wang X, Harris P, Torres V (2003) Inhibition of renal
cystic disease development and progression by a vasopressin V2
receptor antagonist. Nat Med 9:1323–1326
89. Kaariainen H, Koskimies O, Norio R (1988) Dominant and reces-
sive polycystic kidney disease in children: evaluation of clinical
features and laboratory data. Pediatric Nephrol 2:296–302
90. Phillips J, Hopwood D, Loxley R, Ghatora K, Coombes J, Tan Y,
Harrison J, McKitrick D, Holobotvskyy V, Arnolda L, Rangan G
(2007) Temporal relationship between renal cyst development,
hypertension and cardiac hypertrophy in a new rat model of auto-
somal recessive polycystic kidney disease. Kidney Blood Press
Res 30:129–144
91. van Gastel M, Torres V (2017) Polycystic kidney disease and the
vasopressin pathway. Ann Nutr Metab 70(s1):43–50
92. Zittema D, Boertien W, van Beek A, Dullaart R, Franssen C,
de Jong P, Meijer E, Gansevoort R (2012) Vasopressin, copep-
tin, and renal concentrating capacity in patients with autosomal
dominant polycystic kidney disease without renal impairment.
Clin J Am Soc Nephrol 7:906–913
93. Ho T, Godefroid N, Gruzon D, Haymann J, Marechal C, Wang X,
Serra A, Pirson Y, Devuyst O (2012) Autosomal dominant poly-
cystic kidney disease is associated with central and nephrogenic
defects in osmoregulation. Kidney Int 82:1121–1129
94. Torres BL, Grantham JJ (2009) A case for water in the treat-
ment of polycystic kidney disease. Clin J Am Soc Nephrol
2009:1140–1150
95. Torres VE, Harris PC (2014) Strategies targeting cAMP sign-
aling in the treatment of polycystic kidney disease. J Am Soc
Nephrol 25(1):18–32. https ://doi.org/10.1681/ASN.20130 40398
96. Torres VECA, Devuyst O etal (2012) Tolvaptan in patients with
autosomal dominant polycystic kidney disease. New Engl J Med
367:2407–2418
97. Wang CJ, Grantham JJ, Wetmore JB (2013) The medicinal use
of water in renal disease. Kidney Int 84(1):45–53
98. Barash I, Ponda MP, Goldfarb DS, Skolnik EY (2010) A pilot
clinical study to evaluate changes in urine osmolality and urine
cAMP in response to acute and chronic water loading in autoso-
mal dominant polycystic kidney disease. Clin J Am Soc Nephrol
5(4):693–697. https ://doi.org/10.2215/cjn.04180 609
99. Wang CJ, Creed C, Winklhofer FT, Grantham JJ (2011) Water
prescription in autosomal dominant polycystic kidney disease:
a pilot study. Clin J Am Soc Nephrol 6(1):192–197. https ://doi.
org/10.2215/cjn.03950 510
100. Higashihara E, Nutahara K, Tanbo M, Hara H, Miyazaki I, Kob-
ayashi K, Nitatori T (2014) Does increased water intake prevent
disease progression in autosomal dominant polycystic kidney
disease? Nephrol Dial Transpl 29(9):1710–1719. https ://doi.
org/10.1093/ndt/gfu09 3
101. Wong ATY, Mannix C, Grantham JJ, Allman-Farinelli M, Badve
SV, Boudville N, Byth K, Chan J, Coulshed S, Edwards ME,
Erickson BJ, Fernando M, Foster S, Haloob I, Harris DCH, Haw-
ley CM, Hill J, Howard K, Howell M, Jiang SH, Johnson DW,
Kline TL, Kumar K, Lee VW, Lonergan M, Mai J, McCloud P,
Peduto A, Rangan A, Roger SD, Sud K, Torres V, Vliayuri E,
Rangan GK (2018) Randomised controlled trial to determine
the efficacy and safety of prescribed water intake to prevent kid-
ney failure due to autosomal dominant polycystic kidney disease
(PREVENT-ADPKD). BMJ Open 8(1):e018794. https ://doi.
org/10.1136/bmjop en-2017-01879 4
102. Duffey KJ, Davy BM (2015) The healthy beverage index is asso-
ciated with reduced cardiometabolic risk in US adults: a prelimi-
nary analysis. J Acad Nutr Diet 115(10):1682–1689.e1682. https
://doi.org/10.1016/j.jand.2015.05.005
103. Kavouras SA (2019) Hydration, dehydration, underhydration,
optimal hydration: are we barking up the wrong tree? Eur J Nutr
58:471–473. https ://doi.org/10.1007/s0039 4-018-01889 -z
104. Cheuvront SN, Ely BR, Kenefick RW, Sawka MN (2010) Bio-
logical variation and diagnostic accuracy of dehydration assess-
ment markers. Am J Clin Nutr 92(3):565–573
105. Sawka MN, Burke LM, Eichner ER, Maughan RJ, Montain SJ,
Stachenfeld NS (2007) American college of sports medicine
position stand exercise and fluid replacement. Med Sci Sports
Exerc 39(2):377–390
106. Manz F, Wentz A (2003) 24-h hydration status: parameters,
epidemiology and recommendations. Eur J Clin Nutr 57(Suppl
2):10–18
107. Armstrong LE, Maresh CM, Castellani JW, Bergeron MF,
Kenefick RW, LaGasse KE, Riebe D (1994) Urinary indices of
hydration status. Int J Sport Nutr 4(3):265–279
108. Perrier ET, Bottin JH, Vecchio M, Lemetais G (2017) Crite-
rion values for urine-specific gravity and urine color represent-
ing adequate water intake in healthy adults. Eur J Clin Nutr
71(4):561–563. https ://doi.org/10.1038/ejcn.2016.269
109. Perrier ET, Buendia-Jimenez I, Vecchio M, Armstrong LE,
Tack I, Klein A (2015) Twenty-four-hour urine osmolality as
a physiological index of adequate water intake. Dis Markers
2015:231063. https ://doi.org/10.1155/2015/23106 3
110. McKenzie AL, Munoz CX, Ellis LA, Perrier ET, Guelinckx I,
Klein A, Kavouras SA, Armstrong LE (2017) Urine color as
an indicator of urine concentration in pregnant and lactating
women. Eur J Nutr 56(1):355–362. https ://doi.org/10.1007/s0039
4-015-1085-9
111. Guyton AC, Hall JE (2006) Regulation of extracellular fluid
osmolarity and sodium concentration. In: Textbook of medical
physiology. 11 edn, Elsevier: Philadelphia
112. Brenner BM, Rector FC (2008) Brenner & Rector’s The kidney,
8th edn. Saunders, United States
113. Wang Z, Deurenberg P, Wang W, Pietrobelli A, Baumgartner RN,
Heymsfield SB (1999) Hydration of fat-free body mass: review
and critique of a classic body-composition constant. Am J Clin
Nutr 69(5):833–841
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1180 European Journal of Nutrition (2021) 60:1167–1180
1 3
114. Burchfield JM, Ganio MS, Kavouras SA, Adams JD, Gonza-
lez MA, Ridings CB, Moyen NE, Tucker MA (2015) 24-h Void
number as an indicator of hydration status. Eur J Clin Nutr
69(5):638–641. https ://doi.org/10.1038/ejcn.2014.278
115. Tucker MA, Gonzalez MA, Adams JD, Burchfield JM, Moyen
NE, Robinson FB, Schreiber BA, Ganio MS (2016) Reliability
of 24-h void frequency as an index of hydration status when
euhydrated and hypohydrated. Eur J Clin Nutr 70(8):908–911.
https ://doi.org/10.1038/ejcn.2015.233
116. Thomas DR, Cote TR, Lawhorne L, Levenson SA, Rubenstein
LZ, Smith DA, Stefanacci RG, Tangalos EG, Morley JE (2008)
Understanding clinical dehydration and its treatment. J Am
Med Dir Assoc 9(5):292–301. https ://doi.org/10.1016/j.jamda
.2008.03.006
117. Curhan GC, Willett WC, Knight EL, Stampfer MJ (2004) Dietary
factors and the risk of incident kidney stones in younger women:
nurses’ health study II. Arch Intern Med 164(8):885–891
118. Boertien WE, Riphagen IJ, Drion I, Alkhalaf A, Bakker SJ,
Groenier KH, Struck J, de Jong PE, Bilo HJ, Kleefstra N, Gan-
sevoort RT (2013) Copeptin, a surrogate marker for arginine
vasopressin, is associated with declining glomerular filtration
in patients with diabetes mellitus (ZODIAC-33). Diabetologia
56(8):1680–1688. https ://doi.org/10.1007/s0012 5-013-2922-0
119. Enhorning S, Bankir L, Bouby N, Struck J, Hedblad B, Persson
M, Morgenthaler NG, Nilsson PM, Melander O (2013) Copep-
tin, a marker of vasopressin, in abdominal obesity, diabetes and
microalbuminuria: the prospective malmo diet and cancer study
cardiovascular cohort. Int J Obes 37(4):598–603. https ://doi.
org/10.1038/ijo.2012.88
120. Meijer E, Bakker SJ, Halbesma N, de Jong PE, Struck J, Gan-
sevoort RT (2010) Copeptin, a surrogate marker of vasopressin,
is associated with microalbuminuria in a large population cohort.
Kidney Int 77(1):29–36. https ://doi.org/10.1038/ki.2009.397
121. Velho G, Ragot S, El Boustany R, Saulnier PJ, Fraty M, Moham-
medi K, Fumeron F, Potier L, Marre M, Hadjadj S, Roussel R
(2018) Plasma copeptin, kidney disease, and risk for cardiovas-
cular morbidity and mortality in two cohorts of type 2 diabetes.
Cardiovascular diabetology 17(1):110. https ://doi.org/10.1186/
s1293 3-018-0753-5
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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