title: Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial.
abstract: The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland; olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Division of Nephrology, University of Chicago, Chicago, Illinois.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Department of Urology, Kyorin University School of Medicine, Mitaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.affiliation: Department of Medicine, Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland.
authors.forename: Jaime D
authors.initials: JD
authors.lastname: Blais
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
mesh_terms: D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000652:urine*; D000077602:Tolvaptan; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: collecting ducts; cyclic AMP; polycystic kidney disease; vasopressin; water transport