title: Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4.
abstract: The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.
  
  
  
  In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.
  
  
  
  At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.
  
  
  
  Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.|Units of Nephrology and Dialysis.
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.|Units of Nephrology and Dialysis.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Perna
authors.affiliation: Immunohematology and Transfusion Medicine, and.
authors.forename: Luca
authors.initials: L
authors.lastname: Barcella
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Matias
authors.initials: M
authors.lastname: Trillini
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cortinovis
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Claudia Patricia
authors.initials: CP
authors.lastname: Ferrer Siles
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Jorge Arturo
authors.initials: JA
authors.lastname: Reyes Loaeza
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Aparicio
authors.affiliation: Radiology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; and.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fasolini
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Martinetti
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Carrara
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rubis
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Prandini
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caroli
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Antiga
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Remuzzi
authors.affiliation: Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.|Units of Nephrology and Dialysis.|Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000209:etiology; D018450:Disease Progression; D057239:Early Termination of Clinical Trials; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D011446:Prospective Studies; D011507:Proteinuria / Q000139:chemically induced / Q000209:etiology*; D051436:Renal Insufficiency, Chronic / Q000209:etiology*; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus
keywords: Adult; Humans; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Renal Insufficiency; adverse effects; kidney failure, chronic; proteinuria; randomized controlled trials; sirolimus