title: Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial.
abstract: BACKGROUND
  Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function.
  
  
  METHODS
  This randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18-75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692.
  
  
  RESULTS
  We randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0·44 [95% CI 0·24-0·78]; p=0·0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1·17 [0·70-1·95]; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048).
  
  
  CONCLUSIONS
  For the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset.
  
  
  BACKGROUND
  Medical Research Council, Novartis, Renal Association, Kidney Research UK.
authors: Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors: Andrew
authors: A
authors: Howman
authors: Tracey L
authors: TL
authors: Chapman
authors: Maria M
authors: MM
authors: Langdon
authors: Caroline
authors: C
authors: Ferguson
authors: Dwomoa
authors: D
authors: Adu
authors: John
authors: J
authors: Feehally
authors: Gillian J
authors: GJ
authors: Gaskin
authors: David R W
authors: DR
authors: Jayne
authors: Donal
authors: D
authors: O'Donoghue
authors: Michael
authors: M
authors: Boulton-Jones
authors: Peter W
authors: PW
authors: Mathieson
mesh_terms: D002699:Chlorambucil / Q000008:administration & dosage / Q000627:therapeutic use*; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000503:physiopathology; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use*; D016019:Survival Analysis; D006113:United Kingdom
chemical_list: D007166:Immunosuppressive Agents; D002699:Chlorambucil; D016572:Cyclosporine; D011239:Prednisolone