title: Sirolimus therapy to halt the progression of ADPKD.
abstract: Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.
authors.affiliation: Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
authors.forename: Luca
authors.initials: L
authors.lastname: Antiga
authors.forename: Anna
authors.initials: A
authors.lastname: Caroli
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fasolini
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cafaro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ondei
authors.forename: Nadia
authors.initials: N
authors.lastname: Rubis
authors.forename: Olimpia
authors.initials: O
authors.lastname: Diadei
authors.forename: Giulia
authors.initials: G
authors.lastname: Gherardi
authors.forename: Silvia
authors.initials: S
authors.lastname: Prandini
authors.forename: Andrea
authors.initials: A
authors.lastname: Panozo
authors.forename: Rodolfo Flores
authors.initials: RF
authors.lastname: Bravo
authors.forename: Sergio
authors.initials: S
authors.lastname: Carminati
authors.forename: Felipe Rodriguez
authors.initials: FR
authors.lastname: De Leon
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.forename: Monica
authors.initials: M
authors.lastname: Cortinovis
authors.forename: Nicola
authors.initials: N
authors.lastname: Motterlini
authors.forename: Bogdan
authors.initials: B
authors.lastname: Ene-Iordache
authors.forename: Andrea
authors.initials: A
authors.lastname: Remuzzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D018592:Cross-Over Studies; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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