| Objective: Idiopathic membranous nephropathy(IMN)is one of the commonest causes of primary nephrotic syndrome in adults,which is manifested as severe proteinuria and hypoproteinemia.The pathological features were subepithelial immune complex deposition and subsequent thickening of glomerular basement membrane.The natural course of IMN varies.Approximately one-third of affected individuals will have a complete and spontaneous remission of proteinuria,while another third develop persistent proteinuria with long-term preservation of renal function.However,the remaining third of patients will progress to end-stage renal disease(ESRD)in 5-15 years.Immunosuppressive agents in general are shown to prevent renal progression and all-cause mortality in IMN patients with nephrotic syndrome.However,the efficacy and safety of different immunosuppressive treatments have not been systematically assessed and compared.Therefore,a systematic review and network meta-analysis was performed to compare different immunosuppressive treatment in IMN.Methods: Cochrane library,MEDLINE,EMBASE and trial registers were searched for randomized controlled trials(RCT)reporting the treatments for IMN to May 3,2016.Two authors screened studies base on inclusive criteria independently and assessed the methodological quality of the included studies using the Jadad scale and Cochrane Collaboration tool for assessing the risk of bias.Available data and composite endpoints of mortality or the incidence of ESRD,complete or partial proteinuria remission and withdrawal because of treatment adverse events were extracted and compared combining direct and indirect comparison using network meta-analysis.Ranks of different immunosuppressive treatments in the outcomes were analyzed using surface under the cumulative ranking curve(SUCRA).Statistics were conducted using Stata14.0 software.Results: In total,36 RCTs(n=2018)covering 11 treatments were included.Network meta-analysis was performed for the three primary outcomes using consistency model.For all-cause mortality or ESRD,19 studies including 8 types of immunosuppressive therapies were included in the NWM.Compared with non-immunosuppressive treatment,only cyclophosphamide(OR=0.31,95%CI: 0.12-0.81)and chlorambucil(OR=0.33,95%CI: 0.12-0.92)significantly reduced the risk of composite outcome of mortality or ESRD.The SUCRA showed alkylating agents was the best.For complete or partial remission,a total of 31 RCTs including 11 immunosuppressive therapies reported effects.ACTH showed the best effect in reducing proteinuria levels in patients with idiopathic membranous nephropathy(OR = 91.00,95% CI: 5.98-1384.15)followed by cyclophosphamide(OR = 4.29,95% CI: 2.30(OR = 3.10,95% CI: 1.36-7.09),cyclosporine(OR = 2.81,95% CI: 1.00-11.92)and tacrolimus(OR = 3.10,95% CI: 1.36-7.09)CI: 1.08-7.32).Two kinds of calcineurin inhibitors have similar effect comparing with cyclosporine.The sensitivity analysis of high quality studies showed that cyclosporine(OR=5.08,95%CI: 0.92-27.99),cyclophosphamide(OR=3.73,95%CI: 1.85-7.48)and tacrolimus(OR=3.69,95%CI: 1.49-9.14)were top treatments to improve CR or PR,comparing with non-immunosuppressive therapies.A total of 21 RCTs including 9 immunosuppressive agents reported effects on withdrawal from treatment.Compared with the control group,chlorambucil had the highest withdrawal rates(OR=13.73,95%CI 4.23-44.59),followed by MMF(OR=6.17,95%CI 1.10-34.58),mizoribine(OR=4.46,95%CI 1.21-91.66),cyclophosphamide(OR=4.11,95%CI 1.52-11.10)and steroids(OR=3.82,95%CI 1.24-11.75).But tacrolimus and cyclosporine had lower withdrawal rates(OR = 2.17,95% CI: 0.24-19.74 and OR = 2.27,95% CI: 0.21-95.66).Calcineurin inhibitors showed the best tolerance among all immunosuppressive agents.About 10.1% of the patients who treated with immunosuppressive agents had suffer a severe infection,the highest infection rates of the three treatment options were tacrolimus 21.5%(38/177),mycophenolate mofetil 19.7%(14/71)and cyclophosphamide 15.2%(68/448).The patients who treated with cyclosporine had the highest rate of recurrence of proteinuria(21.2%).Conclusions: Only cyclophosphamide and chlorambucil reduce risk of ESRD or death in IMN with nephrotic range proteinuria,however,they both especially chlorambucil had higher risk of drug withdrawal.Tacrolimus and cyclosporine increase the possibility of proteinuria remission with less drug withdrawal,but the long-term efficacy need more research to prove. |
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