title: Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease.
abstract: BACKGROUND
  Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by multitudes of expanding renal cysts associated with mononuclear interstitial infiltrates. Monocyte chemotactic protein-1 is produced in the kidneys and excreted in the urine (uMCP1) of these patients in increased amounts. In the TEMPO 3:4 trial, tolvaptan slowed the rate of increase in total kidney volume (TKV) and the rate of decline in estimated glomerular filtration rate (eGFR). In a sub-analysis, we determined whether tolvaptan administration for up to 3 years changed the urinary excretion of MCP-1 referenced to creatinine in 869 treated subjects compared with 438 placebo subjects.
  
  
  METHODS
  Treatment group differences of uMCP1 at 0.75, 12, 24 and 36 months were evaluated by ANCOVA with factor of treatment and covariate baseline.
  
  
  RESULTS
  At baseline, mean uMCP1 was 429 ± 224 pg/mg in the tolvaptan and 434 ± 233 pg/mg in the placebo groups, ∼4-fold greater than normal. Log uMCP1 associated positively with log TKV ( r = 0.2645, P < 0.0001) and negatively with eGFR ( r = -0.1555 P < 0.0001) and fasting urine osmolality ( r = -0.1933, P < 0.0001). Tolvaptan reduced uMCP1 13.8 ± 4.4% (P < 0.0001) below placebo-treated subjects at 24 months and 14.4 ± 3.7% (P < 0.0001) at 36 months, and to the same extent in females and males. The effect of tolvaptan on uMCP1 excretion at 36 months extended across CKD Stage 1 (11.1 ± 6.4%, P = 0.0595), CKD 2 (13.9 ± 5.4%, P = 0.0050) and CKD 3 (21.4 ± 8.0%, P = 0.0020).
  
  
  CONCLUSIONS
  Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion of MCP-1 relative to placebo.
authors.affiliation: The Kidney Institute, Kansas University Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.affiliation: University of Chicago, Chicago, IL 60637, USA.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Blais
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850, USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.affiliation: University of Zurich, Zürich 8057, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: University of Groningen, Groningen, GR 9713 GZ, The Netherlands.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Kyorin University, Kyorin, 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
authors.initials: H
authors.lastname: Krasa
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.affiliation: Mayo Clinic, Rochester, MN 55901, USA.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
mesh_terms: D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000652:urine; D018932:Chemokine CCL2 / Q000652:urine*; D003404:Creatinine / Q000652:urine; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000652:urine; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000077602:Tolvaptan; D003404:Creatinine
keywords: chemokine; chronic renal disease; disease progression; interstitial inflammation; renal biomarker