title: Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.
abstract: BACKGROUND
  Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30% to 40% of patients progress toward end-stage kidney disease (ESKD) within five to 15 years. The efficacy and safety of immunosuppression for IMN with nephrotic syndrome are still controversial. This is an update of a Cochrane review first published in 2004.
  
  
  OBJECTIVE
  The aim of this review was to evaluate the safety and efficacy of immunosuppressive treatments for adult patients with IMN and nephrotic syndrome. Moreover it was attempted to identify the best therapeutic regimen, when to start immunosuppression and whether the above therapies should be given to all adult patients at high risk of progression to ESKD or only restricted to those with impaired kidney function.
  
  
  METHODS
  We searched Cochrane Renal Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese databases, reference lists of articles, and clinical trial registries to June 2014. We also contacted principal investigators of some of the studies for additional information.
  
  
  METHODS
  Randomised controlled trials (RCTs) investigating the effects of immunosuppression in adults with IMN and nephrotic syndrome.
  
  
  METHODS
  Study selection, data extraction, quality assessment, and data synthesis were performed using the Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.
  
  
  RESULTS
  Thirty nine studies with 1825 patients were included, 36 of these could be included in our meta-analyses. The data from two studies could not be extracted and one study was terminated due to poor accrual. Immunosuppression significantly reduced all-cause mortality or risk of ESKD ((15 studies, 791 patients): RR 0.58 (95% CI 0.36 to 0.95, P = 0.03) and risk of ESKD ((15 studies, 791 patients): RR 0.55, 95% CI 0.31 to 0.95, P = 0.03), increased complete or partial remission ((16 studies, 864 patients): RR 1.31, 95% CI 1.01 to 1.70, P = 0.04), and decreased proteinuria ((9 studies,(393 patients): MD -0.95 g/24 h, 95% CI -1.81 to -0.09, P = 0.03) at the end of follow-up (range 6 to 120 months). However this regimen was associated with more discontinuations or hospitalisations ((16 studies, 880 studies): RR 5.35, 95% CI 2.19 to 13.02), P = 0.0002). Combined corticosteroids and alkylating agents significantly reduced death or risk of ESKD ((8 studies, 448 patients): RR 0.44, 95% CI 0.26 to 0.75, P = 0.002) and ESKD ((8 studies, 448 patients): RR 0.45, 95% CI 0.25 to 0.81, P = 0.008), increased complete or partial remission ((7 studies, 422 patients): RR 1.46, 95% CI 1.13 to 1.89, P = 0.004) and complete remission ((7 studies, 422 patients): RR 2.32, 95% CI 1.61 to 3.32, P < 0.00001), and decreased proteinuria ((6 studies, 279 patients): MD -1.25 g/24 h, 95% CI -1.93 to -0.57, P = 0.0003) at the end of follow-up (range 9 to 120 months). In a population with an assumed risk of death or ESKD of 181/1000 patients, this regimen would be expected to reduce the number of patients experiencing death or ESKD to 80/1000 patients (range 47 to 136). In a population with an assumed complete or partial remission of 408/1000 patients, this regimen would be expected to increase the number of patients experiencing complete or partial remission to 596/1000 patients (range 462 to 772). However this combined regimen was associated with a significantly higher risk of discontinuation or hospitalisation due to adverse effects ((4 studies, 303 patients): RR 4.20, 95% CI 1.15 to 15.32, P = 0.03). Whether this combined therapy should be indicated in all adult patients at high risk of progression to ESKD or only restricted to those with deteriorating kidney function still remained unclear. Cyclophosphamide was safer than chlorambucil ((3 studies, 147 patients): RR 0.48, 95% CI 0.26 to 0.90, P = 0.02). There was no clear evidence to support the use of either corticosteroid or alkylating agent monotherapy. Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. The numbers of corresponding studies related to tacrolimus, mycophenolate mofetil, adrenocorticotropic hormone, azathioprine, mizoribine, and Tripterygium wilfordii are still too sparse to draw final conclusions.
  
  
  CONCLUSIONS
  In this update, a combined alkylating agent and corticosteroid regimen had short- and long-term benefits on adult IMN with nephrotic syndrome. Among alkylating agents, cyclophosphamide was safer than chlorambucil. This regimen was significantly associated with more withdrawals or hospitalisations. It should be emphasised that the number of included studies with high-quality design was relatively small and most of included studies did not have adequate follow-up and enough power to assess the prespecified definite endpoints. Although a six-month course of alternating monthly cycles of corticosteroids and cyclophosphamide was recommended by the KDIGO Clinical Practice Guideline 2012 as the initial therapy for adult IMN with nephrotic syndrome, clinicians should inform their patients of the lack of high-quality evidence for these benefits as well as the well-recognised adverse effects of this therapy. Cyclosporine or tacrolimus was recommended by the KDIGO Clinical Practice Guideline 2012 as the alternative regimen for adult IMN with nephrotic syndrome; however, there was no evidence that calcineurin inhibitors could alter the combined outcome of death or ESKD.
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China, 100853.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Chen
authors.forename: Arrigo
authors.initials: A
authors.lastname: Schieppati
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
authors.forename: Javier
authors.initials: J
authors.lastname: Zamora
authors.forename: Giovanni A
authors.initials: GA
authors.lastname: Giuliano
authors.forename: Norbert
authors.initials: N
authors.lastname: Braun
authors.forename: Annalisa
authors.initials: A
authors.lastname: Perna
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000477:Alkylating Agents / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D009404:Nephrotic Syndrome / Q000150:complications* / Q000188:drug therapy; D011507:Proteinuria / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic
chemical_list: D000305:Adrenal Cortex Hormones; D000477:Alkylating Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine