High Versus Ad Libitum Water Intake in Patients with Autosomal Dominant Polycystic Kidney Disease (DRINK): An Open Label, Randomised Controlled Phase 2 Trial

Background: Vasopressin promotes cyst growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Vasopressin receptor antagonists slow disease progression, but their use is limited by side effects and cost. High water intake suppresses vasopressin production and may provide a viable alternative to pharmacological receptor blockade. We aimed to assess the feasibility of a definitive randomised high water intake trial in ADPKD. Methods: We conducted a phase 2, single-centre open-label randomised controlled trial (NCT02933268). Adults aged 16 years and older with ADPKD and an eGFR20ml/min/1.73m2 were randomly assigned to prescribed high water intake (HW) targeting a urine osmolality of 270mOsm/kg, or ad libitum (AW) intake. The co-primary outcomes were the proportion of participants achieving target urine osmolality and the rate of recruitment. Secondary outcomes included separation between treatment arms, changes in GFR, copeptin, and safety. Findings: 42 participants with a median baseline eGFR 75.8 (IQR 46.5-107.5) ml/min/1.73m2 and urine osmolality 352 (IQR 202-452) mOsm/Kg were enrolled over 12 months and randomised to HW (n=21) or AW (n=21). After 8 weeks, 67% in the HW compared to 24% in the AW group had a urine osmolality of 270mOsm/kg, p=0.001. The median week-8 urine osmolality was significantly higher in the AW compared to HW group (379 IQR 235-503 v 194 IQR 190-438 mOsm/kg, p=0.01). There was no difference in median week 8 plasma copeptin (AW=4.1, IQR 2.9-11.2 vs HW=3.6, IQR 2.7-5.7, p=0.25) and no evidence of acute effects of increased hydration on measured or estimated GFR. Interpretation: It is possible to recruit to and achieve separation between trial arms in urine osmolality in a randomised trial. A definitive trial assessing the effect of high water intake on kidney function in ADPKD is feasible. Clinical Trial Number: NCT02933268 Funding Statement: The study is funded by the British Renal Society and Kidney Care UK (formerly British Kidney Patient Association) grant programme, the PKD Charity, the Addenbrooke’s Charitable Trust and Kidney Research UK. Declaration of Interests: None declared Ethics Approval Statement: DRINK was approved by the East of England Essex Research Committee (16/EE/0026) and the study was overseen by the trial steering committee.