title: Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial.
abstract: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable.
  
  
  
  Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR).
  
  
  
  Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR.
  
  
  
  In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Meijer
authors.affiliation: Division of Nephrology, Emory University School of Medicine, 201 Dowman Drive, Atlanta, Ga. 30322, US.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850 USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.affiliation: Division of Nephrology, Cliniques Universitaires St. Luc, Université Catholique de Louvain Medical School, 10 Avenue Hippocrate 1200, Brussels, Belgium.|Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Häldeliweg 2, 8044 Zürich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Kidney Institute and the Department of Internal Medicine, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 Kansas City, KS, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.affiliation: Department of Urology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo. 181-8611 Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850 USA.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Krasa
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850 USA.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Department of Medicine, Division of Nephrology, TuftsMedical Center, Tufts University School of Medicine, 800 Washington St # 400, Boston, MA 02111, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First St. SW Rochester, MN 55905, USA.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D065092:Antidiuretic Hormone Receptor Antagonists / Q000008:administration & dosage; D001552:Benzazepines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D011446:Prospective Studies; D000077602:Tolvaptan; D016896:Treatment Outcome
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: ADPKD; albuminuria; chronic renal failure; eGFR; vasopressin