Spend just a few minutes scrolling online health sites and one will find experts of every stripe extolling the virtue of hydration—increased consumption of H2O is good for the heart, skin, brain, and, yes, the kidneys. But while increasing water intake does reduces arginine vasopressin and urine osmolality, it does not slow the growth of cysts in persons with autosomal dominant polycystic kidney disease (ADPKD), according to a study published in the new online journal NEJM Evidence.

As Gopala K. Rangan, PhD, of the Michael Stern Laboratory for Polycystic Kidney Disease, at the Westmead Institute for Medical Research, in Sydney, Australia, and colleagues wrote, “prescribed water intake compared with ad libitum water intake in people with ADPKD, although associated with about a 10% incidence of reversible hyponatremia, that led to a sustained increase in urine volume and achieved target urine osmolality in half of the patients did not change MRI-measured kidney volume growth over 3 years. The results of our study do not support the routine use of prescribed enhanced water intake for people with ADPKD.”

The trial, which enrolled 184 patients who were randomized and followed for 3 years, was “one of the largest long-term, multicenter, randomized controlled trials on the effect of prescribed water intake on kidney disease progression. Previous studies on ADPKD were of short duration, were nonrandomized, and did not include a validated disease-specific primary outcome measure. Remarkably, the intervention group in our study achieved a mean 0.6-liter increase in urine volume and a mean 91 mOsmol/kg reduction in urine osmolality that occurred within 12 weeks and was sustained for the entire 3-year period.”

All of the patients had height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and estimated glomerular filtration rate (eGFR) of at least 30 mg/min/1.73 m2, and they were evenly randomized to “prescribed water intake to reduced 24-hour urine osmolality to 270 mOsmol/kg or less or ad libitum water intake irrespective of 24-hour osmolality. The primary endpoint was the percentage of annualized rate of change in height-corrected t0tal kidney volume.”

The average age of patients was 43, and 47.8% of the controls were women, as were 54.3% of the prescribed water group. More than 70% of the participants were White, most had hypertension, about 40% had hematuria, and renal or flank pain was slightly more common among controls. At baseline, the mean 24-hour urine osmolality and median 24-hour urine volume for all participants was “423±165 mOsmol/kg and 2,253 ml (interquartile range, 1,788 to 3,093 ml), respectively,” they wrote.

After 3 years, “the median absolute changes in height-corrected total kidney volume per year were 55.0 ml/m (interquartile range, 30.6 to 100.4 ml/m) in the ad libitum water intake group and 39.0 ml/m (interquartile range, 19.2 to 77.0 ml/m) in the prescribed water intake group. The annualized rate of change in height-corrected total kidney volume (percentage points of baseline kidney volume per year) was 7.8 percentage points per year (95% CI, 6.6 to 9.0) in the ad libitum water intake group versus 6.8 percentage points per year in the prescribed water intake group (95% CI, 5.8 to 7.7). There was no difference in the rate of growth between the prescribed and ad libitum water intake groups (−0.97 percentage points per year; 95% CI, −2.37 to 0.44; P=0.18).”

Additionally, there was no difference in annual rate of decline in eGFR between the groups.

In an editorial published with the study, Louise M. Moist, MD, of the Schulich School of Medicine and Dentistry, Western University, in London, Ontario, Canada, explained that ADPKD patients are currently prescribed “water drinking to suppress agrinine vasopression. 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 nonhemodynamic renal mechanisms. 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.”

But, as logical as that hypothesis was, the trial failed to provide evidence of benefit. Moist suggests that one reason was the patients who were enrolled: their risk of disease progression was low, perhaps too low to demonstrate benefit. Another possible reason: the researchers did not prescribe a great enough increase in water intake, as she points out “the baseline 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). 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 suppression of arginine vasopressin with the addition of more water.”

But perhaps the most important issue was timing: as the trial was underway, the selective vassopressin-2 receptor antagonist tolvaptan, approved for slowing cyst growth in ADPKD, came to market.

“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 prescribed water group,” Moist wrote.

Study limitations include its open-label design, intential nonexclusion of patients who were at target urine osmolality at baseline, possible confounding of changes in urine osmolality by imparired concentrating ability in ADPKD and disease progression, and the inclusion of patients with intermedicate and rapid kidney cyst growth rates.


The study was funded by Funded by the National Health and Medical Research Council of Australia, Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation.

Rangan disclosed grant or contract agreements with Danone, National Health and Medical Council, Otsuka Pharmaceutical, and PKD Australia.

Moist disclosed consultant agreements with AstraZeneca, Bayer, and Otsuka Pharmaceutical.



Peggy Peck, Editor-in-Chief, BreakingMED™

Kaiser Health News

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