Research

JAMA | Original Investigation

Effect of Coaching to Increase Water Intake on Kidney

Function Decline in Adults With Chronic Kidney Disease
The CKD WIT Randomized Clinical Trial
William F. Clark, MD; Jessica M. Sontrop, PhD; Shih-Han Huang, MD, PhD; Kerri Gallo, RN; Louise Moist, MD, MSc;
Andrew A. House, MD; Meaghan S. Cuerden, MSc; Matthew A. Weir, MD, MSc; Amit Bagga, MD;
Scott Brimble, MD; Andrew Burke, MD; Norman Muirhead, MD; Sanjay Pandeya, MD; Amit X. Garg, MD, PhD

Supplemental content
IMPORTANCE In observational studies, increased water intake is associated with better CME Quiz at
kidney function. jamanetwork.com/learning

OBJECTIVE To determine the effect of coaching to increase water intake on kidney function
in adults with chronic kidney disease.

DESIGN, SETTING, AND PARTICIPANTS The CKD WIT (Chronic Kidney Disease Water Intake
Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until
2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease
(estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or
macroalbuminuria) and a 24-hour urine volume of less than 3.0 L.

INTERVENTIONS Patients in the hydration group (n = 316) were coached to drink more water,
and those in the control group (n = 315) were coached to maintain usual intake.

MAIN OUTCOMES AND MEASURES The primary outcome was change in kidney function (eGFR
from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin
concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall
quality of health (0 [worst possible] to 10 [best possible]).

RESULTS Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR,
43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5];
control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of
619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration
group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was −2.2 mL/min/1.73 m2 in
the hydration group and −1.9 mL/min/1.73 m2 in the control group (adjusted between-group
Author Affiliations: London Health
difference, −0.3 mL/min/1.73 m2 [95% CI, −1.8 to 1.2; P = .74]). The mean between-group Sciences Centre, London, Ontario,
differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, Canada (Clark, Sontrop, Huang, Gallo,
−2.2 pmol/L (95% CI, −3.9 to −0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, Moist, House, Cuerden, Weir,
Muirhead, Garg); Department of
0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, −4 to 51; P = .11); and quality of Medicine, Western University,
health, 0.2 points (95% CI, −0.3 to 0.3; P = .22). London, Ontario, Canada (Clark,
Huang, Moist, House, Weir, Bagga,
Muirhead, Garg); Department of
CONCLUSIONS AND RELEVANCE Among adults with chronic kidney disease, coaching to
Epidemiology and Biostatistics,
increase water intake compared with coaching to maintain the same water intake did not Western University, London, Ontario,
significantly slow the decline in kidney function after 1 year. However, the study may have Canada (Sontrop, Moist, Garg);
been underpowered to detect a clinically important difference. Hôtel-Dieu Grace Hospital, Windsor,
Ontario, Canada (Bagga);
Department of Medicine, McMaster
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01766687. University, Hamilton, Ontario, Canada
(Brimble); Guelph General Hospital,
Guelph, Ontario, Canada (Burke);
Halton Healthcare Services, Oakville,
Ontario, Canada (Pandeya).
Corresponding Author: William F.
Clark, MD, Victoria Hospital, 800
Commissioner’s Road E, A2-343,
London, ON, Canada N6A 5W9
JAMA. 2018;319(18):1870-1879. doi:10.1001/jama.2018.4930 (william.clark@lhsc.on.ca).

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 Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease
D
espite widespread interest, little scientific data exist
on the optimal amount of water to drink. The popu-
lar advice to “drink at least 8 glasses of water a day”
originated not from primary research, but from the US Food
and Nutrition Board in 1945, which recommended a daily
water intake of 2.5 L per day and stated that the majority of
this intake could come from food sources.1,2 While many
claims about the benefits of increased water intake remain
untested,2-4 a growing body of evidence suggests that drink-
ing more water may benefit the kidneys.5,6 In animals that
undergo a near complete bilateral nephrectomy, drinking
more water suppresses the plasma concentration of vaso-
pressin and improves creatinine clearance,7,8 and in studies
of humans, drinking more water is associated with better kid-
ney function and a reduced risk of kidney stones. 9 -1 3
Whether increased water intake can benefit patients with
chronic kidney disease remains unknown.
In a 6-week pilot randomized clinical trial of 29 patients
with stage 3 chronic kidney disease, coaching patients to
drink at least 1 additional liter of water per day (in addition to
usual fluid intake) resulted in reduced vasopressin secretion
(as assessed by the plasma concentration of copeptin, a gly-
cosylated peptide that is co-released with vasopressin from
the hypothalamus) compared with patients in the control
group who were coached to maintain usual fluid intake.14,15
Guided by this pilot study, the present 9-center Chronic
Kidney Disease Water Intake Trial (CKD WIT) was conducted
to determine if coaching patients to drink more water slowed
their decline in kidney function over 1 year compared with
those in the control group who were coached to maintain
usual fluid intake.
Methods
Study Design and Oversight
A parallel-group randomized clinical trial was conducted from
April 2013 to June 2017. Ethical approval to conduct this trial
was obtained from Western University’s health sciences re-
search ethics board. All patients provided written informed
consent. The original protocol (Supplement 1) and the statis-
tical analysis plan (Supplement 2) for this trial are available on-
line, the updated protocol was published previously,16 and
changes to the original protocol are summarized in eTable 1 in
Supplement 3. Prespecified and post hoc outcomes are sum-
marized in eTable 2 in Supplement 3 along with the date that
each outcome was added. Study reporting follows recom-
mended guidelines for randomized trials of nonpharmaco-
logic treatments.17
Trial conduct and safety were monitored by an indepen-
dent data and safety monitoring board, which received a
descriptive summary of trial data and adverse events at
intervals of 3 to 9 months, with no planned interim statisti-
cal analysis of the primary or secondary outcomes. The data
and safety monitoring board requested and received access
to data on estimated glomerular filtration rate (eGFR) and
group assignment but did not discuss these data with the
trial investigators.
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Original Investigation Research
Key Points
Question Does drinking more water protect against declining
kidney function in patients with chronic kidney disease?
Findings In this randomized clinical trial that included 631 adult
patients with chronic kidney disease, the 1-year decline in
estimated glomerular filtration rate did not significantly differ
between patients who were coached to drink more water
compared with patients who were coached to maintain their usual
intake (−2.2 vs −1.9 mL/min per 1.73 m2).
Meaning Coaching to increase water intake did not significantly
slow the decline in kidney function in patients with chronic kidney
disease at 1-year follow-up.
Patients, Setting, and Location
Adult patients with stage 3 chronic kidney disease were
recruited from 9 Canadian chronic kidney disease clinics
across southwestern Ontario: London (3 centers), Oakville
(2 centers), Windsor (2 centers), Guelph (1 center), and
Hamilton (1 center). Potentially eligible patients were invited
by their nephrologist to speak with a research assistant who
explained the study, confirmed eligibility (eTable 3 in
Supplement 3), and obtained written informed consent.
Inclusion criteria were stage 3 chronic kidney disease (eGFR
30 to 60 mL/min per 1.73 m2) and an albumin-to-creatinine
ratio of greater than 25 mg/g (2.8 mg/mmol) for women or
greater than 18 mg/g (2.0 mg/mmol) for men (from a random
spot urine sample) or trace protein or greater (from a urine
dipstick).18 Exclusion criteria included self-reported fluid
intake of 10 cups per day or more, a 24-hour urine volume of
3 L or more, a history of kidney stones in the past 5 years,
currently taking lithium or a diuretic above a certain dose
(eTable 3 in Supplement 3), or a prescribed fluid restriction of
less than 1.5 L per day.
After providing written informed consent, patients pro-
vided a prerandomization 24-hour urine sample to confirm
their urine volume was less than 3 L per day (which was an eli-
gibility requirement for randomization).
Randomized Allocation
Once study eligibility was confirmed, a research assistant
contacted each patient by telephone to complete the ran-
domization, and concealed randomized allocation was
implemented by computer-generated randomization while
the patient was on the phone. The randomized sequence
was created by an independent statistician using SAS statis-
tical software version 9.3 and was stratified by center and
sex with a 1:1 allocation using random permuted block sizes
of 4 and 6.
After randomization, research staff and patients were
made aware of group assignment; however, the primary out-
come was an objective measure, outcome assessors (techni-
cians performing the laboratory measurements for the pri-
mary and secondary outcomes) were unaware of the random
allocation, and the trial statistician was blinded to patient
allocation for the primary analysis.
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 Research Original Investigation Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease
Intervention Group
Patients in the hydration group were coached to increase
their water intake by 1.0 to 1.5 L per day (depending on sex
and weight), over and above usual consumed beverages, for
the duration of the 1-year trial (eTable 4 in Supplement 3).
The target water intake was informed by prior literature,9,19-21
patient safety, and what proved feasible in the pilot trial.14,15
A gradual increase in water intake over 2 weeks was advised.
During week 1, patients were instructed to drink an addi-
tional cup of water at breakfast, lunch, and dinner and to
increase to the full amount in week 2. Patients in the hydra-
tion group also received reusable drinking containers and
were mailed 20 vouchers per month, each redeemable for
1.5 L of bottled water.
Control Group
Patients in the control group were coached to continue with
their usual fluid intake or to decrease intake by 0.25 to 0.5 L
per day (1 to 2 cups/d) if their prerandomization 24-hour urine
volume was greater than 1.5 L per day and 24-hour urine
osmolality was less than 500 mOsm/kg.14
Intervention Adherence and Monitoring
To encourage adherence to the assigned intervention and to
minimize cross-group contamination, patients in the hydra-
tion and control groups were individually coached over the
phone at monthly intervals for 12 months after randomiza-
tion using a standardized survey with reference to quantity
of fluid ingested relative to the target intake. Coaching also
included a discussion of urine color charts (showing the
spectrum of diluted to concentrated urine). Intervention
adherence was assessed by 24-hour urine volume (collected
at 6 and 12 months after randomization and measured
by a local laboratory). Adherence was also assessed by
self-reported fluid intake (measured at 3, 6, and 9 months
after randomization).
Data Collection and Measurement
All patients, irrespective of their randomized group assign-
ment, had the same data collection and measurement
schedule (eTable 5 in Supplement 3); more information is
provided in Supplement 1 and in the published protocol.16
Serum creatinine was measured using the isotope dilution
mass spectroscopy–traceable enzymatic method, and the
eGFR was calculated using the Chronic Kidney Disease Epi-
demiology Collaboration (CKD-EPI) equation. 22 Plasma
copeptin concentration was measured from 150-μL blood
samples at enrollment (prerandomization), at the pa-
tients’ next kidney care clinic visit (usually 6 to 7 months
after enrollment), and at 12 months after randomization;
these samples were stored at −80°C and analyzed in batches
using the automated immunofluorescent Copeptin proAVP
assay on the KRYPTOR compact PLUS (BRAHMS GmbH).23
Albuminuria was measured from a 24-hour urine sample
using a standard collection jug within 2 weeks of enrollment
(prerandomization) and again at 6 and 12 months after ran-
domization. Patient-reported quality of health was mea-
sured on a 10-point Likert scale (0 [worst possible] to 10
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[best possible]; item 22 from the RAND Kidney Disease
Quality of Life Short Form).24,25
Outcomes
The prespecified primary outcome was 1-year change in eGFR
from enrollment (prerandomization) to 12 months after
randomization.26,27 Prespecified secondary outcomes were
1-year change in plasma copeptin concentration,28,29 creati-
nine clearance, 24-hour urine albumin, 30 and patient-
reported overall quality of health (Supplement 1 and the pub-
lished protocol16).24,25
Other exploratory outcomes (some prespecified and some
post hoc; eTable 2 in Supplement 3) were 1-year change in
24-hour urine osmolality, creatinine, urea, sodium, and po-
tassium; serum osmolality, creatinine, and urea; blood pres-
sure, body weight, waist circumference, and body mass in-
dex (calculated as weight in kilograms divided by height in
meters squared); and the 6-month change in dietary intake of
protein and sodium.
Sample Size
In a previous longitudinal study of healthy adults free of
chronic kidney disease, those with urine volumes of 3 L per
day or more had a significantly slower eGFR decline than
those with smaller urine volumes (difference, 0.6 mL/min
per 1.73 m2 per year; P = .01).9 Given that in previous studies
of patients with chronic kidney disease the mean decline in
eGFR ranged from 1.5 to 3.5 mL/min per 1.73 m2 (SD range,
3-5) per year,31-33 a minimal clinically important difference
of 1 mL/min per 1.73 m2 was prespecified (a small to moder-
ate effect size) and the target enrollment was 700 patients
(350 per group; assuming a standard deviation of <5; 2-sided
α = .05; power, 80%).
After 3.1 years of recruitment (1.3 years longer than
originally planned), 631 patients were randomized. Enroll-
ment was stopped at this time in order to stay within the study’s
allocated budget (the trial took longer to conduct and cost
was more than originally estimated due to a higher than ex-
pected screen failure rate and the need to expand into 7 addi-
tional centers [eTable 1 in Supplement 3]). The investigators
made this decision in consultation with the data and safety
monitoring board to ensure that patients’ contribution to this
trial would not be compromised by stopping the trial just short
of the enrollment target. One year after the last patient was ran-
domized, 12-month eGFR values for 590 patients (295 per
group) were available, which enabled detection of a between-
group difference of at least 2 mL/min per 1.73 m2 in the mean
change in eGFR over 1 year (based on an observed standard de-
viation of 9 [2-sided α = .05; power, 80%]). No interim analy-
ses of primary or secondary outcomes were performed.
Analysis
Continuous variables are summarized as mean (SD) or as
median (interquartile range [IQR]) as appropriate. No statis-
tical tests were used to compare baseline characteristics.34
For the analysis of the primary outcome, the between-group
difference in eGFR change (hydration minus control) was
estimated using linear regression with adjustment for the
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 Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease
following prespecified covariates measured at baseline: age
(in years), sex, obesity (body mass index ≥30), current
smoker (yes/no), presence of diabetes, and 24-hour urine
albumin (mg/d; log-transformed); and use of an angiotensin-
converting enzyme inhibitor or angiotensin receptor blocker,
diuretic, β-blocker, calcium channel blocker, or statin. 35
Missing baseline data occurred for less than 0.2% of cat-
egorical covariates (if missing, the condition was considered
absent) and was 6% for 24-hour urine albumin (imputed
using fully conditionally specified models36 [eAppendix 1 in
Supplement 3]). Patients who died within 1 year of follow-up
were excluded from the primary and secondary outcome
analyses (12 of 631 patients [1.9%]). Less than 5% of survi-
vors were missing a 12-month eGFR value (±4 months); in
the primary analysis only, missing eGFR data were imputed
using fully conditionally specified models36 (eAppendix 1 in
Supplement 3).
Several supplementary analyses of eGFR change were con-
ducted using nonimputed data: (1) eGFR measured with cys-
tatin C; (2) a longitudinal analysis of change in eGFR over time;
(3) a mixed-effects analysis of eGFR change with a random in-
tercept to account for center; (4) the annual percentage change
([final eGFR−baseline eGFR]÷baseline eGFR); and (5) the pro-
portion of patients with a 1-year eGFR decline of at least 20%.37
To examine the effect of intervention adherence, a prespeci-
fied per-protocol analysis was conducted that excluded the fol-
lowing: (1) patients in the hydration group who did not main-
tain a 24-hour urine volume of at least 0.5 L per day above their
baseline value at 6 and 12 months; (2) patients in the control
group who did not maintain a 24-hour urine volume within
0.5 L per day of their baseline value; and (3) patients who
missed an assessment or whose final urine sample was col-
lected more than 16 months after randomization. Three post
hoc subgroup analyses were conducted for baseline macroal-
buminuria, diabetes, and an eGFR below 45 mL/min per
1.73 m2; these analyses were conducted using linear regres-
sion with an interaction term.
All analyses except the per-protocol supplementary analy-
sis were conducted according to the intention-to-treat prin-
ciple. All tests were 2-sided and conducted at the .05 level of
significance. Formal adjustment for multiple comparisons was
not performed and therefore all analyses of supplementary, sec-
ondary, and other outcomes should be considered explor-
atory. Normally distributed variables were compared using the
t test; non-normally distributed variables were compared using
the Wilcoxon 2-sample test using the normal approximation,
and the 95% CI for the difference between 2 medians was cal-
culated using Hodges-Lehmann estimation. Differences be-
tween categorical variables were calculated using the χ2 test,
and 95% CIs were calculated with a continuity correction. Sta-
tistical analyses were conducted using SAS version 9.3 or later,
SPSS version 24 (IBM SPSS), and R (version 3.2.0).
Results
Trial enrollment began on April 8, 2013, and the last patient
was randomized on May 6, 2016 . The sample flow is shown
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Original Investigation Research
in the Figure. Of 2390 patients assessed for eligibility, 1568
did not meet the study’s eligibility criteria or did not wish to
participate. Of 822 patients who consented, 191 were
excluded before randomization: 76 withdrew for personal
reasons, 2 due to physician decision, 1 died, 47 had a 24-hour
urine volume above 3 L, 31 failed to provide a 24-hour urine
sample, and 34 were ineligible for other reasons (eg, medica-
tion contraindications or chemotherapy). The remaining 631
patients were randomized to the hydration group (n = 316) or
the control group (n = 315). During the 1-year trial period, 12
of 631 patients died (1.9%) (5 [1.6%] in the hydration group
and 7 [2.2%] in the control group); of the 619 survivors, 95%
provided 1-year follow-up measurements (last day of follow-
up, May 25, 2017).
Baseline characteristics of 631 randomized patients are
shown in Table 1. There were no clinically important differ-
ences between randomized groups. Patients had a mean
(SD) age of 65.0 years (11.8); 63.4% were men, 90.6% were
white, 45.6% were obese (body mass index ≥30), 88.1% had
hypertension, and 48.0% had diabetes. The mean (SD)
24-hour urine volume at baseline was 1.9 (0.6) L per day,
eGFR was 43.4 (9.8) mL/min per 1.73 m 2 , and creatinine
clearance was 53.5 (17.4) mL/min per 1.73 m2. Median urine
albumin was 122.8 mg/d (IQR, 34.9-512.0). At baseline, 150
patients in the control group (47.6% of 315) had a urine vol-
ume greater than 1.5 L per day (mean, 2.3 L/d) and a urine
osmolality of less than 500 mOsm/kg (mean, 365 mOsm/kg);
these patients were asked to decrease their water intake by
1 cup per day.
Intervention Adherence
The mean 1-year change in 24-hour urine volume was 0.6 L per
day greater in the hydration group than the control group (95%
CI, 0.5 to 0.7; P < .001), and the mean 9-month change in self-
reported fluid intake was 0.7 L per day greater in the hydra-
tion group than the control group (95% CI, 0.6 to 0.8; P < .001)
(Table 2).
Primary Outcome: Change in eGFR
A scatterplot of the change in eGFR by baseline levels in the hy-
dration and control groups is shown in eFigure 1 in Supplement
3. The mean 1-year decline in eGFR was −2.2 mL/min per
1.73 m2 in the hydration group and −1.9 mL/min per 1.73 m2 in
the control group; the adjusted between-group difference in
change was −0.3 mL/min per 1.73 m2 (95% CI, −1.8 to 1.2; P = .74)
(Table 3).
Results were similar in the unadjusted analysis and
when eGFR was calculated using cystatin C (eTable 6 in
Supplement 3), when eGFR change was analyzed longitudi-
nally (eAppendix 2 in Supplement 3), and in a mixed-effects
model accounting for the effect of center (eTable 7 in
Supplement 3). The mean percentage decline in eGFR from
baseline was 4.6% in the hydration group and 4.4% in the
control group (difference, −0.2 [95% CI, −3.8 to 3.5];
P = .93), and the proportion of patients with an eGFR
decline of at least 20% over 1 year was 21.6% in the hydra-
tion group and 20.7% in the control group (difference, 0.9%
[95% CI, −5.7% to 7.5%]; P = .79) (eTable 8 in Supplement 3).
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 Research Original Investigation Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease

Figure. Flow of Patients Through the Chronic Kidney Disease Water Intake Trial

2390 Individuals approached for

study participationa

1568 Excluded
412 Ineligible
211 Drank more than 10 cups of
water per day
57 Unable to speak or read English
39 Taking a diuretic or lithium
33 Under fluid restriction
72 Other reasonsb
1156 Declined participation
168 Moving, on vacation, or difficulty
getting to laboratories
101 Disliked or unable to drink more water
23 Family situation
864 Other reasonsc

822 Consented

191 Excluded before randomization

631 Randomized
316 Randomized to hydration group
316 Received intervention as
randomized
5 Diede
17 Withdrew
12 Participant decision
5 Physician decision
311 Included in primary analysis
5 Excluded (died)
291 Included in complete case analysis
20 Excluded (missing final eGFR value)
17 Withdrew from study
12 Participant decision
5 Physician decision
3 Did not complete blood test
for eGFR
112 Ineligible to participate
47 Urine sample >3 L/d
31 No urine sample provided
34 Other reasonsd
78 Withdrew from study
76 Participant decision
2 Physician decision
1 Died a
Prescreened by a research assistant
for eligibility.
b
Other reasons: no urine protein,
enrolled in another study, pregnant
or breastfeeding, kidney stones in
the past 5 years, less than 2 years of
315 Randomized to control group
315 Received intervention as life expectancy, and gastrointestinal
randomized issues (eg, inflammatory bowel
disease or Crohn disease).
c
7 Diedf Other reasons: too busy, did not
4 Withdrew (participant decision) want to undergo blood tests, did
not want to undergo 24-hour urine
collections, cancer diagnosis,
physician advised not to participate.
308 Included in primary analysis d
Other reasons: medication
7 Excluded (died) contraindications or chemotherapy.
299 Included in complete case analysis e
Median time to death was 5.1
9 Excluded (missing final eGFR value) months (interquartile range, 3.1-7.3).
4 Withdrew from study (participant f
decision) Median time to death was 7.2
4 Did not complete blood test months (interquartile range,
for eGFR 2.0-10.2).
1 Started dialysis
eGFR indicates estimated glomerular
filtration rate.

Per-Protocol Analysis Subgroup Analyses

Of 316 patients in the hydration group, 89 (28.2%) main-
tained a urine volume that was at least 0.5 L per day greater
than their baseline value at each follow-up assessment. Of 315
patients in the control group, 184 (58.4%) had a urine volume
that remained at least 0.5 L per day less than their baseline
value at each follow-up assessment. In these per-protocol
groups, the 1-year change in 24-hour urine volume was 1.5 L
per day more in the hydration group than in the control group
(95% CI, 1.3 to 1.6; P < .001), and the mean 1-year change in
eGFR was −1.5 mL/min per 1.73 m2 in the hydration group vs
−1.6 mL/min per 1.73 m2 in the control group; the between-
group difference was 0.2 mL/min per 1.73 m2 (95% CI, −1.9 to
2.3; P = .86).
No statistically significant interactions were observed in 3 post
hoc subgroup analyses of patients with and without macroal-
buminuria (eTable 9 in Supplement 3) or diabetes (eTable 10
in Supplement 3), and in those with an eGFR of at least
45 mL/min per 1.73 m2 or less than 45 mL/min per 1.73 m2 at
baseline (eTable 11 in Supplement 3).
Secondary Outcomes
As shown in Table 4, statistically significant between-group
differences were seen for plasma copeptin concentration and
creatinine clearance but not for 24-hour urine albumin
or patient-reported quality of health. The 1-year change in
plasma copeptin concentration was 2.2 pmol/L lower in the

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 Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease Original Investigation Research

Table 1. Baseline Characteristics of Patients in the Chronic Kidney Disease Table 1. Baseline Characteristics of Patients in the Chronic Kidney Disease
Water Intake Trial (N = 631) Water Intake Trial (N = 631) (continued)

Treatment Group Treatment Group

Demographic and Hydration Control Demographic and Hydration Control
Clinical Characteristics (n = 316) (n = 315) Clinical Characteristics (n = 316) (n = 315)
Age, mean (SD), y 64.8 (12.0) 65.2 (11.6) Measures from blood samples,
mean (SD)
Men, No. (%) 200 (63.3) 200 (63.5)
eGFR (creatinine)c, mL/min 43.2 (10.2) 43.7 (9.3)
Race/ethnicity, No. (%)a per 1.73 m2
White 279 (88.3) 293 (93.0) eGFR (cystatin C)d, mL/min 46.7 (19.8) 47.5 (19.3)
per 1.73 m2
South Asian 14 (4.4) 3 (1.0)
Copeptin, pmol/L 16.6 (11.8) 17.8 (13.7)
Black 7 (2.2) 8 (2.5)
Cystatin C, mg/L 1.6 (0.5) 1.6 (0.4)
Other 16 (5.1) 11 (3.5)
Sodium, mEq/L 139.1 (2.7) 139.2 (2.6)
Weight, mean (SD), kg 87.2 (18.9) 87.2 (19.9)
Osmolality, mOsm/kg 300.3 (7.4) 301.2 (8.3)
BMI,b mean (SD) 30.0 (6.0) 29.8 (6.0)
b Urea, mg/dL 28.9 (9.5) 28.6 (10.4)
Obese (BMI ≥30 ), No. (%) 149 (47.2) 139 (44.1)
Measures from 24-h
Current smoker, No. (%) 30 (9.5) 38 (12.1) urine samples
Daily fluid intake, 2.1 (0.8) 2.0 (0.7) Urine volume, mean (SD), L/d 1.9 (0.6) 1.9 (0.6)
mean (SD), L/d
Creatinine, mean (SD), mmol/d 11.9 (4.3) 12.0 (3.7)
Primary etiology
of chronic kidney disease, Osmolality, mean (SD), mOsm/kg 447.4 (140.0) 456.6 (132.9)
No. (%)
Urea, mean (SD), mmol/d 339.6 (129.9) 350.2 (125.7)
Hypertension 127 (40.2) 119 (37.8)
Sodium, mean (SD), mmol/d 145.9 (62.4) 149.2 (62.5)
Diabetes 120 (38.0) 105 (33.3)
Potassium, mean (SD), mmol/d 63.3 (26.6) 63.9 (23.4)
Glomerulonephritis 35 (11.1) 41 (13.0)
Albumin, median (IQR), mg/d 108 (31-522) 150 (40-507)
Autoimmune 15 (4.7) 26 (8.3)
Creatinine clearance, mean (SD), 53.0 (18.7) 54.0 (16.4)
Polycystic kidney disease 9 (2.9) 9 (2.8) mL/min per 1.73 m2
Other/unknown 10 (3.2) 15 (4.8) Medications, No. (%)
Chronic kidney disease ACE inhibitor or angiotensin 217 (68.7) 211 (67.0)
stage, No. (%) receptor blocker
c
eGFR ≥45 mL/min 141 (44.6) 148 (47.0) Statin 203 (64.2) 211 (67.0)
per 1.73 m2
Calcium channel blockers 134 (42.4) 125 (39.7)
Urine albumin <30 mg/d 28 (8.9) 39 (12.4)
β-Blockers 124 (39.2) 127 (40.3)
Urine albumin 30-300 mg/d 58 (18.4) 65 (20.6)
Diuretic 133 (42.1) 113 (35.9)
Urine albumin >300 mg/d 49 (15.5) 33 (10.5)
eGFRc<45 mL/min 175 (55.4) 167 (53.0) Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index;
per 1.73 m2 CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated
glomerular filtration rate; IQR, interquartile range.
Urine albumin <30 mg/d 31 (9.8) 33 (10.5)
SI conversion factors: To convert serum urea to mmol/L, multiply by 0.357.
Urine albumin 30-300 mg/d 77 (24.4) 63 (20.0)
a
Self-reported race/ethnicity was collected and recorded by a research
Urine albumin >300 mg/d 53 (16.8) 63 (20.0)
assistant using prespecified categories; black/white racial origin is needed for
Comorbidities within the calculation of eGFR.
last 10 y, No. (%) b
BMI was calculated as weight in kilograms divided by height in meters squared.
Hypertension 278 (88.3) 278 (88.3) c
Calculated using the CKD-EPI creatinine equation.
Hyperlipidemia 211 (67.2) 206 (65.8) d
Calculated using the CKD-EPI cystatin C equation.
Diabetes 166 (52.7) 137 (43.5)
Malignancy 60 (19.1) 72 (23.0)
hydration group than the control group (95% CI, −3.9 to −0.5;
Coronary artery disease 64 (20.4) 67 (21.3)
P = .01), and the 1-year change in creatinine clearance was
Cerebrovascular/transient 36 (11.5) 45 (14.3)
ischemic attack 3.6 mL/min per 1.73 m2 higher in the hydration group than the
Peripheral vascular disease 28 (8.9) 28 (8.9) control group (95% CI, 0.8 to 6.4; P = .01). The between-
Chronic obstructive 45 (14.2) 43 (13.7) group difference in the 1-year change in urine albumin was
pulmonary disease 6.8 mg/d (95% CI, −3.9 to 50.8; P = .11), and the between-
Transplant 13 (4.1) 20 (6.3) group difference in the 1-year change in quality of life was 0.2
Congestive heart failure 19 (6.0) 11 (3.5) units (95% CI, −0.3 to 0.3; P = .22).
Family history of hypertension 181 (57.3) 177 (56.2)
or kidney failure, No. (%)
Systolic blood pressure, 140.8 (19.1) 136.8 (17.2)
Other Outcomes
mean (SD), mm Hg The mean 1-year change in 24-hour urine osmolality, creati-
Diastolic blood pressure, 79.2 (10.3) 77.7 (10.9) nine, urea, sodium, and potassium are shown in eTable 12 in
mean (SD), mm Hg
Supplement 3; between-group differences were −75.6 mOsm/kg
(continued) (95% CI, −98.2 to −53.0; P < .001) for urine osmolality,
0.8 mmol per day (95% CI, 0.3 to 1.4; P = .003) for creatinine,

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 Research Original Investigation Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease

Table 2. Change in 24-Hour Urine Volume and Self-reported Fluid Intakea

Mean (SD)
Hydration Group Control Group Mean Difference
(n = 291) (n = 299) (95% CI)b P Valueb
Urine volume, L/d a
All analyses followed the
Prerandomization 1.9 (0.6) 1.9 (0.6) intention-to-treat principle.
b
6 Month 2.5 (0.9) 1.9 (0.6) Between-group differences in
change were analyzed using the
12 Month 2.5 (0.8) 1.9 (0.7)
independent-samples t test.
12-Month change (95% CI) 0.6 (0.5 to 0.7)c −0.04 (0.0 to 0.1)c 0.6 (0.5 to 0.7) <.001 c
Change was calculated as the final
Self-reported fluid intake, L/d value minus the prerandomization
Prerandomization 2.1 (0.8) 2.0 (0.7) value; restricted to patients who
provided follow-up data within 8 to
3 Month 2.8 (0.9) 2.0 (0.6)
16 months of randomization
6 Month 2.8 (0.8) 2.1 (0.7) (excluding 12 patients who died
9 Month 2.8 (0.8) 2.0 (0.6) during the 12-month trial period
[5 in the hydration group and 7 in
9-Month change (95% CI) 0.7 (0.6 to 0.8)c 0.0 (−0.1 to 0.1)c 0.7 (0.6 to 0.8) <.001
the control group]).

Table 3. Primary Outcome: 1-Year Change in Estimated Glomerular Filtration Ratea

Mean (95% CI)

Hydration Group Control Group Adjusted Between-Group Difference
eGFR, mL/min per 1.73 m2 (n = 311) (n = 308) in Changeb (95% CI) P Value
Prerandomization 43.3 (42.1 to 44.4) 43.6 (42.6 to 44.7)
12 Months 41.0 (39.5 to 42.6) 41.7 (40.3 to 43.1)
Change −2.2 (−3.3 to −1.1)c −1.9 (−2.9 to −0.9)c −0.3 (−1.8 to 1.2) .74
Abbreviation: eGFR, estimated glomerular filtration rate. current smoker, presence of diabetes, urinary albumin (mg/d)
a
Analyses exclude 12 patients who died during the 12-month trial period (log-transformed), and use of the following medications: an angiotensin-
(5 in the hydration group; 7 in the control group); all analyses followed the converting enzyme inhibitor or angiotensin receptor blocker, diuretic,
intention-to-treat principle. Fully conditionally specified models were used to β-blocker, calcium channel blocker, and statin.
c
impute missing 12-month eGFR values for 29 patients. The mean change in eGFR (12-month value minus the prerandomization value)
b
The adjusted between-group difference in eGFR change was analyzed using was calculated within each of 20 imputed data sets, and the mean was
linear regression, adjusted for age (in years), sex, obesity (body mass index calculated using the imputed data set means.
ⱖ30 [calculated as weight in kilograms divided by height in meters squared]),

25.4 mmol per day (95% CI, 5.1 to 45.6; P = .01) for urea,
21.9 mmol per day (95% CI, 10.3 to 33.6; P < .001) for sodium,
and 2.8 mmol per day (95% CI, −1.6 to 7.1; P = .22) for potas-
sium. No statistically significant differences were seen be-
tween groups for the 1-year change in serum osmolality,
creatinine, or urea (eTable 13 in Supplement 3); blood pres-
sure, weight, waist circumference, or body mass index (eTable
14 in Supplement 3); or the 6-month change in dietary intake
of protein and sodium (eTable 15 in Supplement 3).
Adverse Events and Serum Sodium Monitoring
The data and safety monitoring board performed 5 reviews
of trial safety and integrity during the recruitment period
and recommended that the trial continue. During the trial,
52 adverse events occurred among 42 (13%) patients in the
hydration group (including 5 deaths [3 additional deaths
occurred between 13 and 16 months]) and 66 events
occurred among 51 (16%) patients in the control group
(including 7 deaths [3 additional deaths occurred between
13 and 16 months]). All adverse events were investigated,
and no events were attributed to the intervention. Patients’
serum sodium levels were monitored also at 3-month inter-
vals (eTable 16 in Supplement 3). Serum sodium concentra-
tion declined to less than 130 mEq/L in 3 patients in the
hydration group and in 1 participant in the control group;
each case was investigated and reported to the participant’s
physician; all values normalized by the next study visit.
The 1-year change in serum sodium was 0.5 mEq/L lower
in the hydration group than the control group (95% CI, −1.0
to −0.04; P = .04).
Discussion
In this randomized clinical trial of approximately 600 pa-
tients with stage 3 chronic kidney disease, drinking more wa-
ter (compared with usual fluid intake alone) did not slow the
decline in eGFR over 1 year. This trial had 80% statistical power
to detect a between-group difference in eGFR change of
2 mL/min per 1.73 m2. Findings from the primary intention-
to-treat analyses were consistent with the per-protocol analy-
ses for which there was a greater separation in 24-hour urine
volume between groups.
The absence of an effect of drinking more water on eGFR
may be interpreted in several ways. First, increased water
intake may not protect against declining kidney function,
and the results of prior observational studies may have
been confounded.9-11
Second, there may have been an effect, but the study
was underpowered to identify it as statistically significant

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 Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease Original Investigation Research

Table 4. Secondary Outcomes: 1-Year Change in Plasma Copeptin, Creatinine Clearance, 24-Hour Urine Albumin,
and Patient-Reported Overall Quality of Healtha
Hydration Group Control Group Between-Group
(n = 291) (n = 299) Difference in Changeb (95% CI) P Valueb
Plasma copeptin, mean (SD), pmol/L
Prerandomization 17.4 (12.4) 17.5 (13.0)
12 Month 16.1 (13.5) 18.3 (13.6)
Change (95% CI) −1.4 (−2.7 to −0.0)c 0.8 (−0.3 to 1.9)c −2.2 (−3.9 to −0.5) .01
Creatinine clearance, mean (SD), mL/min
per 1.73 m2
Prerandomization 52.5 (17.1) 54.6 (15.6)
12 Month 53.1 (19.7) 51.6 (18.9)
Change (95% CI) 0.6 (−1.6 to 2.7)c −3.0 (−4.9 to −1.2)c 3.6 (0.8 to 6.4) .01
Urine albumin, mean (SD), mg/d
Prerandomization 139 (49 to 425) 108 (32 to 606)
12 Month 142 (38 to 509) 103 (32 to 497)
Change (95% CI) 7 (−4.1 to 16.2)c 0.2 (−7.0 to 4.6)c 6.8 (−3.9 to 50.8) .11
Quality of healthd
Prerandomization 7.3 (1.6) 7.3 (1.6)
12 Month 7.2 (1.9) 7.1 (1.8)
Change (95% CI) −0.0 (−0.3 to 0.2)c −0.2 (−0.4 to −0.0)c 0.2 (−0.3 to 0.3) .22
Abbreviation: IQR, interquartile range. data); CIs for the difference between 2 medians were calculated using
a
All analyses followed the intention-to-treat principle. No adjustment was Hodges-Lehmann estimation.
c
made for multiple comparisons; therefore all results should be interpreted Change was calculated as the 12-month value minus the prerandomization
as exploratory. value; restricted to patients who provided follow-up data within 8 to 16
b
Between-group differences in change were analyzed using the months of randomization (excluding 12 patients who died during the 12-mo
independent-samples t test (for normally distributed data) or the Wilcoxon trial period [5 in the hydration group and 7 in the control group]).
d
2-sample test using the normal approximation (for non-normally distributed Measured on a 10-point Likert scale (0 [worst possible] to 10 [best possible]).

(this study was underpowered to detect a between-group
difference less than 2 mL/min per 1.73 m2); however, the 1-year
decline in eGFR was slightly greater in the hydration group,
suggesting a possible effect in the opposite direction to that
originally hypothesized.
Third, although the hydration group achieved a signifi-
cantly increased fluid intake and decreased copeptin concen-
trations relative to the control group, perhaps a greater differ-
ence in water intake is needed to produce a measurable effect
on eGFR (although the per-protocol analysis was consistent
with the intent-to-treat analysis).
Fourth, more than 1 year of follow-up may be needed to
detect an effect on eGFR. In a clinical trial of patients with
autosomal dominant polycystic kidney disease treated with
Tolvaptan (a vasopressin V2-receptor antagonist) vs placebo,
between-group differences in kidney function did not
emerge until 24 to 36 months after randomization.38 Simi-
larly, a 7-year observational study of 2000 healthy adults
showed less eGFR decline with larger urine outputs. 9
Although patients in the present trial will undergo an addi-
tional 12 months of follow-up to evaluate 2-year eGFR
change, hydration coaching stopped at 12 months, which
may negatively affect patients’ adherence to their random
allocation.16
A marked incongruence was observed between the 1-year
change in eGFR and creatinine clearance. The between-
group difference in the 1-year change in GFR estimated
with serum creatinine was −0.3 mL/min per 1.73 m2 and with
serum cystatin C was −0.2 mL/min per 1.73 m2 (P > .05); how-
ever, the 1-year change in creatinine clearance was signifi-
cantly higher in the hydration group relative to the control
group (the between-group difference was 3.5 mL/min per
1.73 m2 [P = .01]). The latter finding appeared to be driven
by an increased urinary excretion of creatinine in the hydra-
tion group relative to the control group (eTable 12 in Supple-
ment 3). Three explanations for this finding were considered.
Given that the urinary excretion of urea and sodium were
also significantly increased in the hydration group relative to
the control group (eTable 12 in Supplement 3), the possibility
of systematic urine collection errors was considered; how-
ever, urine osmolality and plasma copeptin both decreased
significantly more in the hydration group relative to the con-
trol group, suggesting that patients were following their
randomly assigned intervention. In addition, an increased
urinary excretion of creatinine, urea, and sodium may reflect
an increase in weight (eTable 14 in Supplement 3) or intake of
protein and sodium (eTable 15 in Supplement 3); however, no
between-group differences in these variables were observed,
although perhaps there were dietary changes that went unre-
corded. Also, it is possible that patients in the hydration
group had an increased urinary flow rate, which has been
shown to cause increased tubular secretion and decreased
reabsorption of urinary solutes (specifically creatinine and
urea).39,40 The clinical significance of an increased urinary
flow rate is unknown and further research is needed to better
understand this finding and the underlying physiology.

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 Research Original Investigation Effect of Increased Water Intake on Kidney Function Decline in Chronic Kidney Disease

Limitations Third, the generalizability of trial findings may be limited

This study has several limitations. First, despite the efforts of
dieticians and research assistants who coached patients in the
hydration group to drink 1.0 to 1.5 L of water per day (depend-
ing on sex and weight), mean urine volume in the hydration
group increased by only 0.6 L per day (2.4 cups) relative to the
control group. This highlights how difficult it would be to
achieve a large sustained increase in water intake in routine
practice. However, the increased water intake achieved in this
trial was sufficient to lower vasopressin secretion, as as-
sessed by plasma copeptin concentrations (the 1-year change
in plasma copeptin was 2.3 pmol/L lower in the hydration group
than the control group [P = .009]).
Second, although the magnitude of eGFR decline was
0.3 mL/min per 1.73 m2 greater in the hydration group rela-
tive to the control group, the 95% CI around this estimate
spanned −1.8 to 1.2, and the study was underpowered to de-
tect the prespecified minimal clinically important difference
of 1 mL/min per 1.73 m2; therefore, trial findings should be in-
terpreted as null but potentially underpowered.
by enrollment restricted to patients in Southwestern Ontario,
Canada (a northern region with a temperate climate) in which
90% of the patients were white.
Fourth, the use of estimated rather than measured GFR
represents an important source of measurement error in this
study. Exogenously measured GFR may be more sensitive to
changes in kidney function; however, measurement proto-
cols are more invasive and costly, which may be considered
unacceptable to patients.
Conclusions
Among adults with stage 3 chronic kidney disease, coaching
to increase water intake compared with coaching to main-
tain the same water intake did not significantly slow the
decline in kidney function after 1 year. However, the study
may have been underpowered to detect a clinically impor-
tant difference.

ARTICLE INFORMATION
Accepted for Publication: March 29, 2018.
Author Contributions: Drs Clark and Sontrop had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Clark, Sontrop, Huang, Gallo,
Moist, House, Weir, Garg.
Acquisition, analysis, or interpretation of data: Clark,
Sontrop, Huang, Gallo, House, Cuerden, Weir,
Bagga, Brimble, Burke, Muirhead, Pandeya, Garg.
Drafting of the manuscript: Clark, Sontrop,
Huang, Garg.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Sontrop, Cuerden, Garg.
Obtained funding: Clark, Sontrop.
Administrative, technical, or material support: Clark,
Huang, Gallo, Moist, Weir, Bagga, Burke,
Muirhead, Garg.
Supervision: Clark, Huang, Gallo, Moist, Weir,
Brimble, Muirhead, Pandeya.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Clark
reports receipt of an unrestricted grant, personal
fees (scientific advisory board), and travel support
from Danone Research. Dr Sontrop reports other
(travel support) from Danone Research. Dr Huang
reports receipt of a grant from Danone Research.
Dr Moist reports other (travel support and serving
as chair of the ISN/Danone Hydration for Kidney
Health Research Initiative) from Danone Nutrica.
No other disclosures were reported.
Funding/Support: This study was funded by
Danone Research and the Program of Experimental
Medicine, Western University, Canada. Thermo
Fisher Scientific provided the instrumentation,
assay reagent, and disposables for the analysis
copeptin. Dr Garg was supported by the Dr Adam
Linton Chair in Kidney Health Analytics, and a
Clinician Salary Award from the Canadian Institutes
of Health Research.
Role of Funder/Sponsor: Danone Research
requested that this study include the measure of
creatinine clearance as a secondary outcome; aside
from this, the study sponsors had no role in the
design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
Additional Contributions: Michael Walsh, MD, PhD
(McMaster University), and Daniel G. Biche, MD
(University of Montreal), served on the data and
safety monitoring board for this trial. Ivan Tack, MD,
PhD (Toulouse Hospital), provided useful insight on
renal physiology. None of these individuals received
compensation for their contribution. We also
acknowledge the 631 patients without whom this
investigation would not be possible.
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