title: Tolvaptan in patients with autosomal dominant polycystic kidney disease.
abstract: BACKGROUND
  The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.
  
  
  METHODS
  In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.
  
  
  RESULTS
  Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).
  
  
  CONCLUSIONS
  Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. torres.vicente@mayo.edu
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.forename: Holly B
authors.initials: HB
authors.lastname: Krasa
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
mesh_terms: D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009929:Organ Size / Q000187:drug effects; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012964:Sodium / Q000097:blood; D000077602:Tolvaptan; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan; D012964:Sodium