Everolimus in patients with autosomal dominant polycystic kidney disease.
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.)
Walz
Gerd
G
Renal Division, University Hospital Freiburg, Hugstetter St., 55 79106 Freiburg, Germany. gerd.walz@uniklinik-freiburg.de
Budde
Klemens
K
Mannaa
Marwan
M
Nürnberger
Jens
J
Wanner
Christoph
C
Sommerer
Claudia
C
Kunzendorf
Ulrich
U
Banas
Bernhard
B
Hörl
Walter H
WH
Obermüller
Nicholas
N
Arns
Wolfgang
W
Pavenstädt
Hermann
H
Gaedeke
Jens
J
Büchert
Martin
M
May
Christoph
C
Gschaidmeier
Harald
H
Kramer
Stefan
S
Eckardt
Kai-Uwe
KU
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
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