Published November 4, 2021

NEJM Evid 2022; 1 (1)

DOI: 10.1056/EVIDe2100027

EDITORIAL

Can Additional Water a Day Keep the Cysts Away,

in Patients with Polycystic Kidney Disease?
Louise M. Moist, M.D.

A
mong patients with autosomal dominant polycystic kidney disease (ADPKD),
there is sufficient evidence to support prescribed water drinking to suppress argi-
nine vasopressin.1 The reasoning goes like this: Elevated arginine vasopressin
levels, commonly found in ADPKD, promote cell proliferation and kidney cyst formation
through their effects on glomerular hemodynamics, arterial blood pressure, and nonhemo-
dynamic renal mechanisms.2 Therefore, if a patient with ADPKD could drink enough water
to suppresses arginine vasopressin release, cyst growth would be attenuated, thereby
reducing the decline in kidney function over time.3

This hypothesis was tested by Rangan et al.4 in a randomized controlled trial of coached,
increased water drinking published in this issue of NEJM Evidence. The investigators
hypothesized that the coached, increased water intake would be sufficient to lower urine
osmolality below 270 mOsmol/kg, which is generally accepted to be a threshold to sup-
press arginine vasopressin release, and thus decrease kidney cyst growth compared with
patients who were not coached to drink more water. Over 3 years of follow-up, despite a
mean 0.6-liter increase in urine volume and a 91-mOsmol/kg reduction in urine osmolality
that occurred within 12 weeks and was sustained for the entire 3 years, the authors report
no difference in cyst growth as measured by magnetic resonance imaging. The annualized
height-corrected kidney volume, which is an index of cyst growth, was not different clini-
cally and statistically between the two treatment groups (0.97% per year less; 95% confi-
dence interval, 22.37 to 0.44%; P50.18). Moreover, there was no difference in serum
copeptin concentration, a surrogate marker of arginine vasopressin levels, between the two
groups. Similarly, there was no difference in the annual decline in the estimated glomeru-
lar filtration rate, mean systemic arterial pressure, spot urine albumin-to-creatinine ratio,
or kidney pain.

Although this study does not support the use of prescribed increased water intake in
ADPKD, we are left with three important questions: First, was enough water intake pre-
scribed and/or achieved in the appropriate at-risk population? Second, can increased water The author affiliations are listed at
the end of the article.
intake, adequate to suppress the secretion of arginine vasopressin, be achieved and sus-
Dr. Louise M. Moist can be
tained? Third, will additional studies of increased water intake require comparison to or contacted at louise.moist@lhsc.on.
the addition of tolvaptan? ca or at Department of Medicine,
Schulich School of Medicine and
Dentistry, Western University, 800
Why did the trial fail to meet its goals? First, the authors included patients at lower risk of Commissioners Rd., Room A2-338,
disease progression. Approximately 30% of patients in the study by Rangan et al.4 had a London, ON N6A5W9, Canada.

NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org by Emmanuel Hernandez on October 7, 2023. For personal use only.
No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society.
height-corrected total kidney volume in Mayo imaging
subclass category 1B, which is a low risk category for
chronic kidney disease (CKD) progression regardless of
intervention.5 The rate of change in kidney volume and
glomerular filtration rate progresses in a nonlinear man-
ner, with greater growth and progression over time.6
Because many of the patients had a low risk of cyst pro-
gression and there was insufficient follow-up time to
observe a treatment effect, the possibility of a type II error
(i.e., a false-negative result) seems real.7 Second, the base-
line median fluid intake in this trial was 2.3 liters per day,
which exceeds the daily fluid intake of the average person
(1.5 to 1.9 liters per day).8 Because many patients with a
baseline urine osmolality of less than 300 mOsmol/kg
were included in the trial, there may have been a “floor
effect” that reduced the likelihood of any further suppres-
sion of arginine vasopressin with the addition of more
water. Third, while the trial was underway, tolvaptan, a
selective vasopressin 2 receptor antagonist, was approved
for the indication of slowing cyst growth in patients with
ADPKD. All patients in this study were offered tolvaptan
treatment, and eight patients started taking tolvaptan (five
in the coached water group and three in the control
group). The addition of tolvaptan may have attenuated the
therapeutic effects of additional water intake in the pre-
scribed water group.
If the above issues could be overcome, does a prescrip-
tion to drink more water, being less expensive and more
available than tolvaptan, make sense? Most importantly,
can people sustain the prescribed level of water intake?
In the study by Rangan et al.,4 the prescribed water
group received resource-intensive coaching from highly
skilled dieticians, including education on food and water
intake and physical activity. Urine volumes, osmolality,
and patient-centered goal setting were reinforced by tele-
health visits, direct messaging, and patient visits. Despite
these efforts, the prescribed water group’s mean urine
osmolality was 328 mOsmol/kg, on average less than the
target of 270 mOsmol/kg or lower, and only 52.3% of
patients who were prescribed water met the treatment
adherence criteria for 24-hour urine osmolality of
300 mOsmol/kg or less for more than 50% of the time
points. When questioned, the proportion of patients stat-
ing that the prescribed water intake intervention could
not be maintained lifelong increased from 8.8% at week
26 to 20.8% at week 156. Other researchers have had
similar results with coached water drinking. In the CKD
Water Intake Trial (ClinicalTrials.gov NCT01766687),
the baseline 24-hour urine volume was lower at 1.9
NEJM EVIDENCE
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org by Emmanuel Hernandez on October 7, 2023. For personal use only.
No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society.
liters.8 Patients were coached to increase water intake by
1.0 to 1.5 liters per day and they achieved an increase of
only 0.6 liters per day, similar to the study by Rangan
et al.,4 highlighting the difficulty of sustaining a large
increase in water intake.
Tolvaptan has differing effects on water and osmolality
hemostasis compared with water drinking, as recently
described by Bankir et al.9 These effects may help to
explain the difference in patients’ tolerability of higher
levels of water intake while taking tolvaptan. The use of
tolvaptan in further water intake studies in ADPKD will
need to be considered.
Rangan and colleagues4 are to be congratulated for their
valiant efforts in completing this study and indicating the
safety of this additional water intake in patients with
ADPKD. Before one rechallenges additional water intake
in a higher-risk population or with the addition of or com-
parison to tolvaptan, the question remains of how one sus-
tains long-term behavior change without the benefit or
reinforcement of symptom reduction. This question will
require the engagement of social scientists as we gain fur-
ther evidence of the importance of lifestyle modifications.
Disclosure
Author disclosures and other supplementary materials are available at
evidence.nejm.org.
Author Affiliations
Department of Medicine, Schulich School of Medicine and Dentistry,
Western University, London, Ontario, Canada
Author disclosures and other supplementary material
are available with the full text of this article at
evidence.nejm.org.
References
1. Torres VE. Vasopressin in chronic kidney disease: an elephant in the
room? Kidney Int 2009;76:925-8.
2. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly
regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol
2008;19:102-8.
3. Torres VE, Harris PC. Strategies targeting cAMP signaling in the
treatment of polycystic kidney disease. J Am Soc Nephrol 2014;25:
18-32.
2
4. Rangan GK, Wong ATY, Munt A, et al. Prescribed water intake 7. Torres VE, Chapman AB, Devuyst O, et al.; TEMPO 3:4 Trial Inves-
in autosomal dominant polycystic kidney disease. NEJM Evid. DOI: tigators. Tolvaptan in patients with autosomal dominant polycystic
10.1056/EVIDoa2100021. kidney disease. N Engl J Med 2012;367:2407-18.

5. Irazabal MV, Rangel LJ, Bergstralh EJ, et al.; CRISP Investigators. 8. Clark WF, Sontrop JM, Huang SH, et al. Effect of coaching to increase
Imaging classification of autosomal dominant polycystic kidney dis- water intake on kidney function decline in adults with chronic
ease: a simple model for selecting patients for clinical trials. J Am kidney disease: the CKD WIT randomized clinical trial. JAMA 2018;319:
Soc Nephrol 2015;26:160-72. 1870-9.

6. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and func- 9. Bankir L, Guerrot D, Bichet DG. Vaptans or voluntary increased
tional outcomes in autosomal dominant polycystic kidney disease. hydration to protect the kidney: how do they compare? Nephrol Dial
Clin J Am Soc Nephrol 2012;7:479-86. Transplant 2021;gfab278 10.1093/NDT/GFAB278.

NEJM EVIDENCE 3
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org by Emmanuel Hernandez on October 7, 2023. For personal use only.
No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society.