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      Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

      research-article
      * , , * , , * , * , , * , * , * , * , * , § , * , * , * , * , * , * , * , * , * , * , , ,
      Clinical Journal of the American Society of Nephrology : CJASN
      American Society of Nephrology
      randomized controlled trials, sirolimus, kidney failure, chronic, adverse effects, proteinuria, Adult, Humans, Polycystic Kidney, Autosomal Dominant, Prospective Studies, Renal Insufficiency

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          Abstract

          Background and objectives

          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.

          Design, setting, participants, & measurements

          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.

          Results

          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.

          Conclusions

          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.

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          Author and article information

          Journal
          Clin J Am Soc Nephrol
          Clin J Am Soc Nephrol
          clinjasn
          cjn
          CJASN
          Clinical Journal of the American Society of Nephrology : CJASN
          American Society of Nephrology
          1555-9041
          1555-905X
          6 May 2016
          22 February 2016
          : 11
          : 5
          : 785-794
          Affiliations
          [* ]Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy;
          Units of []Nephrology and Dialysis,
          []Immunohematology and Transfusion Medicine, and
          [§ ]Radiology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; and
          []Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
          Author notes

          P.R., G.G., and N.P. contributed equally to this work.

          Correspondence: Prof. Giuseppe Remuzzi, IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri,” Centro Anna Maria Astori, Science and Technology Park, Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy. Email: giuseppe.remuzzi@ 123456marionegri.it
          Article
          PMC4858487 PMC4858487 4858487 09900915
          10.2215/CJN.09900915
          4858487
          26912555
          19fba900-4c2a-4220-9e83-87ed32970378
          Copyright © 2016 by the American Society of Nephrology
          History
          : 23 September 2015
          : 26 January 2016
          Page count
          Figures: 4, Tables: 4, Equations: 0, References: 35, Pages: 10
          Categories
          Original Articles
          Clinical Nephrology
          Custom metadata
          May 06, 2016

          randomized controlled trials,sirolimus,kidney failure, chronic,adverse effects,proteinuria,Adult,Humans,Polycystic Kidney, Autosomal Dominant,Prospective Studies,Renal Insufficiency

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