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

Abstract

Background and objectives: 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.

Design, setting, participants, & measurements: 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.

Results: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m²) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone.

Conclusions: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Keywords: ADPKD; clinical trial; diabetes insipidus; diuretics; hydrochlorothiazide; metformin; receptors; vasopressin.

Graphical abstract

Figure 1.

Design of the clinical and experimental study. (A) Design of the clinical randomized, controlled, crossover trial that included 13 patients with autosomal dominant polycystic kidney disease (ADPKD). Treatments are in random order. (B) Design of the experimental study that included 88 mice, of which 83 had ADPKD. Mice were treated with tamoxifen at postnatal day 18 (P18) and P19 to inactivate Pkd1. Drug treatment was started at P36: tolvaptan, tolvaptan plus hydrochlorothiazide (HCT), HCT, or no treatment. Animals were euthanized at P117. met, metformin.

Figure 2.

Urine volume and plasma copeptin concentration during the various treatment phases. Treatments were given in random order. (A) The 24-hour urine volume over the different treatment periods. (B) Plasma copeptin over the different treatment periods. The difference between HCT metformin versus placebo was tested. BL, baseline. **P=0.01; ***P<0.01.

Figure 3.

Aquaresis in mice. (A) Water intake (measured daily during the experiment), with the first measured time point at P37. (B) Urine volume measured at day 90 in a metabolic cage. Both tolvaptan (Tolv) and Tolv plus HCT were statistically significant different from untreated (P<0.001 for both; not shown). *P<0.05.

Figure 4.

Disease progression in mice. (A) Total kidney weight (KW; left panel) and total KW-body weight (BW) ratio (right panel). (B) Transversal midslices of the right kidney stained with periodic acid–Schiff. (C) Analyses of transversal midslices for cyst count, total cystic area, and cystic index (proportion of total area consisting of cysts as a percentage). WT, wild type. *P=0.05 compared with untreated cystic mice, Mann–Whitney U test; **P=0.01 compared with untreated cystic mice, Mann–Whitney U test; ***P<0.001 compared with untreated cystic mice, Mann–Whitney U test.