title: Everolimus in patients with autosomal dominant polycystic kidney disease.
abstract: BACKGROUND
  Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth.
  
  
  METHODS
  In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months.
  
  
  RESULTS
  Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups.
  
  
  CONCLUSIONS
  Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)
authors.affiliation: Renal Division, University Hospital Freiburg, Hugstetter St., 55 79106 Freiburg, Germany. gerd.walz@uniklinik-freiburg.de
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Marwan
authors.initials: M
authors.lastname: Mannaa
authors.forename: Jens
authors.initials: J
authors.lastname: Nürnberger
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: Bernhard
authors.initials: B
authors.lastname: Banas
authors.forename: Walter H
authors.initials: WH
authors.lastname: Hörl
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Arns
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Jens
authors.initials: J
authors.lastname: Gaedeke
authors.forename: Martin
authors.initials: M
authors.lastname: Büchert
authors.forename: Christoph
authors.initials: C
authors.lastname: May
authors.forename: Harald
authors.initials: H
authors.lastname: Gschaidmeier
authors.forename: Stefan
authors.initials: S
authors.lastname: Kramer
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D000328:Adult; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood / Q000652:urine; D018450:Disease Progression; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000517:prevention & control; D008297:Male; D009929:Organ Size / Q000187:drug effects; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D002784:Cholesterol; D000068338:Everolimus; D003404:Creatinine; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus