title: Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.
abstract: BACKGROUND
  Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria.
  
  
  METHODS
  In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m(2) or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m(2)). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473.
  
  
  RESULTS
  Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio [HR] 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m(2) (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02).
  
  
  CONCLUSIONS
  Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population.
  
  
  BACKGROUND
  Canadian Institutes of Health Research.
authors.affiliation: Department of Medicine, University of Ottawa, Ottawa, ON, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada; Kidney Research Centre, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, ON, Canada. Electronic address: gknoll@toh.on.ca.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Knoll
authors.affiliation: Department of Medicine, University of Ottawa, Ottawa, ON, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Michaël
authors.initials: M
authors.lastname: Chassé
authors.affiliation: Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Hebert
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Wells
authors.affiliation: Division of Nephrology, Department of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: Tibbles
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Darin
authors.initials: D
authors.lastname: Treleaven
authors.affiliation: Division of Nephrology, Department of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Holland
authors.affiliation: Division of Nephrology, Department of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: White
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, ON, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Muirhead
authors.affiliation: Division of Nephrology, Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cantarovich
authors.affiliation: Division of Nephrology, Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Bryce
authors.initials: B
authors.lastname: Kiberd
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sita
authors.initials: S
authors.lastname: Gourishankar
authors.affiliation: Division of Nephrology, Department of Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Division of Nephrology, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Prasad
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, Toronto, ON, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Cole
authors.affiliation: Department of Renal Medicine, Auckland City Hospital and Department of Medicine, Auckland University, Auckland, New Zealand.
authors.forename: Helen
authors.initials: H
authors.lastname: Pilmore
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, ON, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cronin
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Debora
authors.initials: D
authors.lastname: Hogan
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Tim
authors.initials: T
authors.lastname: Ramsay
authors.affiliation: Division of Nephrology, Department of Medicine, St Paul's Hospital, Vancouver, BC, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Gill
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D017257:Ramipril / Q000627:therapeutic use*; D012307:Risk Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017257:Ramipril