title: Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function.
abstract: BACKGROUND
  A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR.
  
  
  METHODS
  Clinical trial with comparisons before and after treatment.
  
  
  METHODS
  Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting.
  
  
  METHODS
  Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively).
  
  
  RESULTS
  Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers).
  
  
  METHODS
  GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression.
  
  
  RESULTS
  In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron.
  
  
  CONCLUSIONS
  Limited sample size, no control group.
  
  
  CONCLUSIONS
  In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.
authors.affiliation: Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Boertien
authors.affiliation: Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Meijer
authors.affiliation: Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: de Jong
authors.affiliation: Department of Neuroscience, Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: ter Horst
authors.affiliation: Department of Neuroscience, Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Renken
authors.affiliation: Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: van der Jagt
authors.affiliation: Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Kappert
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Haemoscan bv, Groningen, the Netherlands.
authors.forename: Gerwin E
authors.initials: GE
authors.lastname: Engels
authors.affiliation: Haemoscan bv, Groningen, the Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Oeveren
authors.affiliation: AdrenoMed AG, Hennigsdorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Oberdhan
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Krasa
authors.affiliation: Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: r.t.gansevoort@umcg.nl.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005919:Glomerular Filtration Rate; D006020:Glycopeptides / Q000097:blood; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D009994:Osmolar Concentration; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D012720:Severity of Illness Index; D000077602:Tolvaptan; D016896:Treatment Outcome
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D015415:Biomarkers; D006020:Glycopeptides; C048197:copeptins; D000077602:Tolvaptan
keywords: Autosomal dominant polycystic kidney disease (ADPKD); disease progression; drug efficacy; glomerular filtration rate (GFR); kidney function; tolvaptan; vasopressin V(2) receptor antagonist