{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:48:20Z","timestamp":1786373300639,"version":"build-2736575974"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","funder":[{"DOI":"10.13039\/501100002997","name":"Dutch Kidney Foundation","doi-asserted-by":"publisher","award":["18OKG04"],"award-info":[{"award-number":["18OKG04"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2022,4]]},"abstract":"\n Background and objectives<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Design, setting, participants, & measurements<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Patients (age 45\u00b18 years, 54% women, measured GFR of 55\u00b111 ml\/min per 1.73 m\n 2<\/jats:sup>\n ) had a baseline urine volume on tolvaptan of 6.9\u00b11.4 L\/24 h. Urine volume decreased to 5.1 L\/24 h (\n P<\/jats:italic>\n <0.001) with hydrochlorothiazide and to 5.4 L\/24 h (\n P<\/jats:italic>\n <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 \u201cno treatment\u201d on markers of disease progression (kidney weight,\n P<\/jats:italic>\n =0.003 and cystic index,\n P<\/jats:italic>\n =0.04) and superior or equal to tolvaptan alone.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Podcast<\/jats:title>\n This article contains a podcast at https:\/\/www.asn-online.org\/media\/podcast\/CJASN\/2022_03_21_CJN11260821.mp3<\/jats:p>\n <\/jats:sec>","DOI":"10.2215\/cjn.11260821","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T14:45:12Z","timestamp":1647873912000},"page":"507-517","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":36,"title":["Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD"],"prefix":"10.2215","volume":"17","author":[{"given":"Bart J.","family":"Kramers","sequence":"first","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris W.","family":"Koorevaar","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maatje D.A.","family":"van Gastel","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"van Goor","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-2440","authenticated-orcid":false,"given":"Kenneth R.","family":"Hallows","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California"},{"name":"University of Southern California\/University Kidney Research Organization Kidney Research Center, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-3730","authenticated-orcid":false,"given":"Hiddo L.","family":"Heerspink","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University, Hospital Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California"},{"name":"University of Southern California\/University Kidney Research Organization Kidney Research Center, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter N.","family":"Leonhard","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorien J.M.","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiedong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan J.","family":"Touw","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University, Hospital Groningen, Groningen, The Netherlands"},{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron T.","family":"Gansevoort","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The 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