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

2018 ◽  
Author(s):  
Ragada El-Damanawi ◽  
Michael Lee ◽  
Tess Harris ◽  
Laura B. Mader ◽  
Simon Bond ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Phase 2 ◽  
Polycystic Kidney ◽  
Open Label ◽  
Phase 2 Trial ◽  
Ad Libitum ◽  
Autosomal Dominant Polycystic Kidney ◽  
Randomised Controlled

scholarly journals High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial

QJM ◽  
2019 ◽  
Vol 113 (4) ◽  
pp. 258-265 ◽  
Author(s):  
R El-Damanawi ◽  
M Lee ◽  
T Harris ◽  
L B Cowley ◽  
S Bond ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Water Intake ◽  
Autosomal Dominant ◽  
High Water ◽  
Feasibility Trial ◽  
Polycystic Kidney ◽  
High Water Intake ◽  
Ad Libitum ◽  
Autosomal Dominant Polycystic Kidney

Abstract Background Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. Aims Assess the feasibility of a definitive randomized high water intake trial in ADPKD. Methods In this prospective open-label randomized 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). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. Results We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9–107.2] vs. AW 75.8 [IQR 59.0–111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190–438] vs. AW 350 [IQR 240–452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190–438] vs. 379 [IQR 235–503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270–4295] vs. 1920 [IQR 1670–2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. Conclusion DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

scholarly journals Long-Term Administration of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

2018 ◽  
Vol 13 (8) ◽  
pp. 1153-1161 ◽  
Author(s):  
Marie E. Edwards ◽  
Fouad T. Chebib ◽  
Maria V. Irazabal ◽  
Troy G. Ofstie ◽  
Lisa A. Bungum ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Confidence Interval ◽  
Polycystic Kidney Disease ◽  
Risk Ratio ◽  
Autosomal Dominant ◽  
Baseline Risk ◽  
Polycystic Kidney ◽  
Open Label ◽  
Autosomal Dominant Polycystic Kidney

Background and objectivesIn the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy.Design, setting, participants, & measurementsOne hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up.ResultsPatients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m2 per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m2 per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m2 per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment.ConclusionsFollow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

scholarly journals Pro: Tolvaptan delays the progression of autosomal dominant polycystic kidney disease

2018 ◽  
Vol 34 (1) ◽  
pp. 30-34 ◽  
Author(s):  
Vicente E Torres
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Polycystic Kidney ◽  
Open Label ◽  
In Vivo Models ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACT No treatment until now has directly targeted the mechanisms responsible for the development and growth of cysts in autosomal dominant polycystic kidney disease (ADPKD). Strong rationale and preclinical studies using in vitro and in vivo models justified the launching of two large phase 3 clinical trials of tolvaptan in early and later stages of ADPKD. Their design was based on preliminary studies informing on the pharmacokinetics, pharmacodynamics, short-term safety and self-reported tolerability in patients with ADPKD. Tolvaptan slowed kidney growth in the early stage and estimated glomerular filtration rate decline in early and later stages of the disease. All participants had the opportunity to enroll in open-label extension trials to ascertain long-term safety and efficacy. In a single-center analysis of long-term outcomes, the effect of tolvaptan was sustained and cumulative over time supporting a disease-modifying effect of tolvaptan in ADPKD. In the countries where tolvaptan has been approved by regulatory agencies, patients with rapidly progressive ADPKD should be informed about the option of treatment including possible benefits and risks. If a decision to initiate treatment is made, prescribing physicians should educate the patients on the prevention of aquaresis-related adverse events and should be vigilant in the surveillance and management of the potential tolvaptan hepatotoxicity. Other vasopressin V2 receptor antagonists, possibly without potential hepatotoxicity, alternative strategies targeting vasopressin and combination with other drugs able to enhance the efficacy or reduce the aquaresis associated with tolvaptan, deserve further study.

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