title: Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience.
abstract: OBJECTIVE
  Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models.
  
  
  METHODS
  This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes.
  
  
  RESULTS
  Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01).
  
  
  CONCLUSIONS
  ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.
authors: Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
authors: Eiji
authors: E
authors: Higashihara
authors: Vicente E
authors: VE
authors: Torres
authors: Arlene B
authors: AB
authors: Chapman
authors: Jared J
authors: JJ
authors: Grantham
authors: Kyongtae
authors: K
authors: Bae
authors: Terry J
authors: TJ
authors: Watnick
authors: Shigeo
authors: S
authors: Horie
authors: Kikuo
authors: K
authors: Nutahara
authors: John
authors: J
authors: Ouyang
authors: Holly B
authors: HB
authors: Krasa
authors: Frank S
authors: FS
authors: Czerwiec
mesh_terms: D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006727:Hormone Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007564:Japan; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009656:North America; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011446:Prospective Studies; D013997:Time Factors; D000077602:Tolvaptan; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D006727:Hormone Antagonists; D000077602:Tolvaptan