Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial

The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ame...

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Published in:Clinical journal of the American Society of Nephrology 2022-04, Vol.17 (4), p.507-517
Main Authors: Kramers, Bart J, Koorevaar, Iris W, van Gastel, Maatje D A, van Goor, Harry, Hallows, Kenneth R, Heerspink, Hiddo L, Li, Hui, Leonhard, Wouter N, Peters, Dorien J M, Qiu, Jiedong, Touw, Daan J, Gansevoort, Ron T, Meijer, Esther
Format: Article
Language:English
Subjects:
Adult
Animals
Antidiuretic Hormone Receptor Antagonists - adverse effects
Antidiuretic Hormone Receptor Antagonists - therapeutic use
Cross-Over Studies
Female
Humans
Hydrochlorothiazide - pharmacology
Hydrochlorothiazide - therapeutic use
Kidney - drug effects
Kidney - physiopathology
Male
Metformin - pharmacology
Metformin - therapeutic use
Mice
Middle Aged
Original
Polycystic Kidney, Autosomal Dominant - drug therapy
Polyuria - chemically induced
Polyuria - prevention & control
Quality of Life
Receptors, Vasopressin - therapeutic use
Tolvaptan - adverse effects
Tolvaptan - therapeutic use
Treatment Outcome
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Summary:The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m ) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (
ISSN:1555-9041
1555-905X
1555-905X
DOI:10.2215/CJN.11260821