title: Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.
abstract: OBJECTIVE
  To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.
  
  
  METHODS
  Systematic review and meta-analysis of individual patient data.
  
  
  METHODS
  Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.
  Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.
  
  
  RESULTS
  The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.
  
  
  CONCLUSIONS
  Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada University of Ottawa, Ottawa, ON, Canada gknoll@ottawahospital.on.ca.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Knoll
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Madzouka B
authors.initials: MB
authors.lastname: Kokolo
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Ranjeeta
authors.initials: R
authors.lastname: Mallick
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beck
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Chieny D
authors.initials: CD
authors.lastname: Buenaventura
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada University of Ottawa, Ottawa, ON, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Ducharme
authors.affiliation: Cairo Kidney Center, Cairo University, Cairo, Egypt.
authors.forename: Rashad
authors.initials: R
authors.lastname: Barsoum
authors.affiliation: Limites Medical Research, Vacallo Switzerland.
authors.forename: Corrado
authors.initials: C
authors.lastname: Bernasconi
authors.affiliation: University of Manitoba, Department of Pediatrics and Child's Health, Winnipeg, MB, Canada.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Blydt-Hansen
authors.affiliation: Department of Nephrology and Transplantation, Lund University, Malmo, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.affiliation: Hospital do Rim e Hipertensao, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Felipe
authors.affiliation: Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Firth
authors.affiliation: Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.affiliation: Maastricht University Medical Centre, Maastricht, Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Gelens
authors.affiliation: Department of Nephrology, Saint-Louis Hospital, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Glotz
authors.affiliation: Division of Nephrology, Hospital of J.W. Goethe, Frankfurt, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gossmann
authors.affiliation: Department of Surgery, University of Munich, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Guba
authors.affiliation: Cairo Kidney Center, Cairo University, Cairo, Egypt.
authors.forename: Ahmed Ali
authors.initials: AA
authors.lastname: Morsy
authors.affiliation: Clinic of Dermatology, Venerology and Allergology, JW Goethe Clinic, University of Frankfurt, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Salgo
authors.affiliation: Division of Nephrology, Hospital of J.W. Goethe, Frankfurt, Germany.
authors.forename: Earnst H
authors.initials: EH
authors.lastname: Scheuermann
authors.affiliation: Hospital do Rim e Hipertensao, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco-Silva
authors.affiliation: Department of Nephrology, Institutu Klinicke a Experimentalni Mediciny, Prague, Czech Republic.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vitko
authors.affiliation: University of Cambridge, Department of Surgery, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Watson
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON, Canada University of Ottawa, Ottawa, ON, Canada.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fergusson
mesh_terms: D006084:Graft Rejection / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000401:mortality / Q000601:surgery*; D016030:Kidney Transplantation / Q000401:mortality; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020123:Sirolimus / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus