Background: Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake (HWI) as an alternative to pharmacological vasopressin blockade is supported by patients. However the feasibility, safety and adherence-promoting strategies required to deliver this were unknown. The aim of this thesis was to assess the feasibility of a definitive randomised HWI trial in ADPKD.

Methods: and materials: The work consisted of; 1) the SIPs study was an online survey developed in collaboration with the PKD charity, and administered to ADPKD subjects to inform current water intake practices and research willingness, and identify the potential design challenges of a randomised HWI trial, 2) Retrospective ADPKD cohort studies included analyses of data from the UK National Registry of Rare Kidney Diseases (RaDaR) and the Cambridge renal genetics (RGTD) clinic to provide information on the patterns and predictors of kidney disease progression, and 3) the DRINK study was a prospective open-label randomised trial. Adult ADPKD patients with eGFR ≥20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤ 270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Smartphone technology was used to facilitate adherence, self-monitoring and remote data capture through the DRINK and SPLASH study apps. Primary outcomes were the proportion achieving target UOsm and the study recruitment rate. Secondary outcomes included changes in GFR, copeptin, adherence and safety. A bespoke ADPKD Pain Assessment Tool (APAT) was formulated and administered longitudinally to participants to ascertain reliability and to provide pilot data on ADPKD pain.

Results and Conclusion: The DRINK study achieved successful sustained recruitment indicating that a multi-centre large scale trial would be feasible. The study also confirmed that HWI was a feasible intervention, and that the adherence-promoting methods used resulted in a separation between treatment arms that was of sufficient magnitude to drive clinically meaningful differences in kidney function endpoints for future definitive trials. Observational studies using RaDaR and RGTD cohort data identified risk factors for disease progression consistent with previously observed data, providing the basis for the eligibility criteria that would allow enrichment of the target trial population. Furthermore, assessing the rate of disease progression along with the absence of acute GFR effects in the DRINK study enabled determinations of the optimal primary study outcomes, treatment effect sizes, likely sample size and trial duration. All of these components are critical to the design of a definitive interventional ADPKD trial. Finally, the APAT demonstrated good acceptability and reliability and represents a valuable standardised tool for future ADPKD pain studies. The clinical utility of the tool has been recognised by the National Institute of Health Research (NIHR) through a successful grant award to use the APAT for a large multi-centre observational ADPKD study.