Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD

Abstract

Background and objectivesThe 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, & measurementsWe 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.ResultsPatients (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.ConclusionsBoth 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.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3

Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease

“…Whether this can be achieved by limiting protein as well as by limiting salt intake is the subject of clinical investigation [ 42 ]. Experimental evidence suggests that co-prescription with metformin also reduces polyuria during tolvaptan treatment [ 43 ], possibly by a vasopressin-independent upregulation of AQP-2 channels in the collecting duct [ 44 ]. However, in a small-scale cross-over study, the tolerability of metformin appeared less than that of hydrochlorothiazide due to gastrointestinal side effects [ 45 ], and consequently, metformin did not improve quality of life [ 43 ].…”

“…Experimental evidence suggests that co-prescription with metformin also reduces polyuria during tolvaptan treatment [ 43 ], possibly by a vasopressin-independent upregulation of AQP-2 channels in the collecting duct [ 44 ]. However, in a small-scale cross-over study, the tolerability of metformin appeared less than that of hydrochlorothiazide due to gastrointestinal side effects [ 45 ], and consequently, metformin did not improve quality of life [ 43 ]. A third method might be to co-prescribe a thiazide diuretic, such as hydrochlorothiazide.…”

“…The compensatory increase in salt and water reabsorption in the proximal tubule then results in a decreased urinary volume. In two small-scale clinical trials, this strategy resulted in a significant decrease in urinary volume and an improved quality of life in patients on tolvaptan [ 43 , 46 ]. This was corroborated in an experimental study that suggested that co-treatment with a thiazide diuretic may also increase the renoprotective efficacy of tolvaptan [ 43 ].…”

“…In two small-scale clinical trials, this strategy resulted in a significant decrease in urinary volume and an improved quality of life in patients on tolvaptan [ 43 , 46 ]. This was corroborated in an experimental study that suggested that co-treatment with a thiazide diuretic may also increase the renoprotective efficacy of tolvaptan [ 43 ]. Whether such a strategy also has longer-term effects in human ADPKD is going to be investigated in a large-scale clinical trial that is due to start in 2022 [ 24 ].…”

Dietary Aspects and Drug-Related Side Effects in Autosomal Dominant Polycystic Kidney Disease Progression

“…Interestingly, both hydrochlorothiazide and metformin reduced urine volume after 2 weeks of follow-up (hydrochlorothiazide also improved the quality of life and biomarkers of kidney damage). In addition, a long-term follow-up of mice showed that hydrochlorothiazide reduced polyuria in tolvaptan-treated animals [ 65 ]. Although there is no strong evidence for recommending thiazides as an aquaretic effect attenuator, in a larger published observational study, Kramers et al showed that its use was safe in terms of kidney outcomes, so it can be used at least as a second-line antihypertensive [ 66 ].…”