Sirolimus therapy to halt the progression of ADPKD.
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.
Perico
Norberto
N
Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Antiga
Luca
L
Caroli
Anna
A
Ruggenenti
Piero
P
Fasolini
Giorgio
G
Cafaro
Mariateresa
M
Ondei
Patrizia
P
Rubis
Nadia
N
Diadei
Olimpia
O
Gherardi
Giulia
G
Prandini
Silvia
S
Panozo
Andrea
A
Bravo
Rodolfo Flores
RF
Carminati
Sergio
S
De Leon
Felipe Rodriguez
FR
Gaspari
Flavio
F
Cortinovis
Monica
M
Motterlini
Nicola
N
Ene-Iordache
Bogdan
B
Remuzzi
Andrea
A
Remuzzi
Giuseppe
G
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
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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