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Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis.

ABSTRACT: OBJECTIVES:This study aimed to compare the effectiveness of 13 types of immunosuppressive agents used to treat idiopathic membranous nephropathy (IMN) in adults with nephrotic syndrome. DESIGN:Systematic review and network meta-analysis. DATA SOURCES:PubMed, EMbase, Cochrane Library, Web of Science, Clinical trials, SinoMed, Chinese Biomedicine, CNKI, WanFang and Chongqing VIP Information databases were comprehensively searched until February 2018. ELIGIBILITY CRITERIA:Randomised clinical trials (RCTs) comparing the effects of different immunosuppressive treatments in adult patients with IMN and nephrotic syndrome were included, and all included RCTs had a study-duration of at least 6?months. DATA EXTRACTION AND SYNTHESIS:Two reviewers independently screened articles, extracted data and assessed study quality. Standard pairwise meta-analysis was performed using DerSimonian-Laird random-effects model. RESULTS:This study ultimately included 48 RCTs with 2736 patients and 13 immunosuppressive agents. The network meta-analysis results showed that most regimens, except for leflunomide (LEF), mizoribine (MZB) and steroids (STE), showed significantly higher probabilities of total remission (TR) when compared with non-immunosuppressive therapies (the control group),with risk ratios (RRs) of 2.71 (95% CI) 1.81 to 4.06)for tacrolimus+tripterygium wilfordii (TAC+TW), 2.16 (1.27 to 3.69) foradrenocorticotropic hormone, 2.02 (1.64 to 2.49) for TAC, 2.03 (1.13 to3.64) for azathioprine (AZA), 1.91 (1.46 to 2.50) for cyclosporine (CsA), 1.86 (1.44 to2.42) for mycophenolate mofetil (MMF), 1.85 (1.52 to 2.25) for cyclophosphamide (CTX),1.81 (1.10 to 2.98) for rituximab (RIT), 1.80 (1.38 to 2.33) for TW, 1.72 (1.35 to 2.19) for chlorambucil. As for 24 hours UTP, the direct andindirect comparisons showed that AZA (standard mean difference (SMD), -1.02(95% CI -1.90 to -0.15)), CsA (SMD, -0.70 (95% CI -1.33 to -0.08)),CTX (SMD, -1.01 (95% CI -1.44 to -0.58)), MMF (SMD, -0.98 (95% CI -1.64 to -0.32)), MZB (SMD, -0.97 (95% CI -1.90 to-0.04]), TAC (SMD, -1.16 (95% CI -1.72 to -0.60)) and TAC+TW(SMD, -2.03 (95% CI -2.94 to -1.12)) could significantly superior thancontrol, except for chlorambucil, LEF, RIT and STE. Thechanges of serum creatinine (Scr) was not significantly different between eachtreatments of immunosuppressive agents and the control, except for STE whichhas the possibility of increasing Scr (SMD, 1.00 (95% CI 0.36 to 1.64)).Comparisons among all treatments of immunosuppressive agents showed nostatistical significance in the outcome of relapse. A drenocorticotropichormone (85.1%) showed the lowest probability of relapse under the cumulativeranking curve values among all immunosuppressants. Infection,gastrointestinal symptoms, and bone marrow suppression were the common adverseevents associated with most of the immunosuppressive therapies. CONCLUSIONS:This study demonstrates that TAC+TW, TAC and CTX are superior to other immunosuppressive agents in terms of TR and 24?hours UTP. Moreover, they are all at risk of infection, gastrointestinal symptoms, and myelosuppression. Furthermore, TAC could increase the risk of glucose intolerance or new-onset diabetes mellitus. Conversely, STE alone, LEF and MZB seem to have little advantage in clinical treatment of IMN. PROSPERO REGISTRATION NUMBER:CRD42018094228.

SUBMITTER: Zheng Q

PROVIDER: S-EPMC6738938 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis.

Zheng Qiyan Q Yang Huisheng H Liu Weijing W Sun Weiwei W Zhao Qing Q Zhang Xiaoxiao X Jin Huanan H Sun Luying L

BMJ open 20190911 9

<h4>Objectives</h4>This study aimed to compare the effectiveness of 13 types of immunosuppressive agents used to treat idiopathic membranous nephropathy (IMN) in adults with nephrotic syndrome.<h4>Design</h4>Systematic review and network meta-analysis.<h4>Data sources</h4>PubMed, EMbase, Cochrane Library, Web of Science, Clinical trials, SinoMed, Chinese Biomedicine, CNKI, WanFang and Chongqing VIP Information databases were comprehensively searched until February 2018.<h4>Eligibility criteria</ ...[more]

PMID: 31511292

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Project description:Background: Immunosuppressants have been applied in the remedy of idiopathic membranous nephropathy (IMN) extensively. Nevertheless, the efficacy and safety of immunosuppressants do not have final conclusion. Thus, a pairwise and network meta-analysis (NMA) was carried out to seek the most recommended therapeutic schedule for patients with IMN. Methods: Randomized controlled trials (RCTs) including cyclophosphamide (CTX), mycophenolate mofetil (MMF), tacrolimus-combined mycophenolate mofetil (TAC + MMF), cyclosporine (CsA), tacrolimus (TAC), leflunomide (LEF), chlorambucil (CH), azathioprine (AZA), adrenocorticotropic hormone (ACTH), non-immunosuppressive therapies (CON), steroids (STE), mizoribine (MZB), and rituximab (RIT) for patients with IMN were checked. Risk ratios (RRs) and standard mean difference (SMD) were reckoned to assess dichotomous variable quantities and continuous variable quantities, respectively. Total remission (TR) and 24-h urine total protein (24-h UTP) were compared using pairwise and NMA. Then interventions were ranked on the basis of the surface under the cumulative ranking curve (SUCRA). Results: Our study finally included 51 RCTs and 12 different immunosuppressants. Compared with the CON group, most regimens demonstrated better therapeutic effect in TR, with RR of 2.1 (95% CI) (1.5-2.9) for TAC, 1.9 (1.3-2.8) for RIT, 2.5 (1.2-5.2) for TAC + MMF, 1.9 (1.4-2.7) for CH, 1.8 (1.4-2.4) for CTX, 2.2 (1.0-4.7) for ACTH, 1.6 (1.2-2.1) for CsA, 1.6 (1.0-2.5) for LEF, and 1.6 (1.1-2.2) for MMF. In terms of 24-h UTP, TAC (SMD, -2.3 (95% CI -3.5 to -1.1)), CTX (SMD, -1.7 (95% CI -2.8 to -0.59)), RIT (SMD, -1.8 (95% CI -3.5 to -0.11)), CH (SMD, -2.4 (95% CI -4.3 to -0.49)), AZA (SMD, --4.2 (95% CI -7.7 to -0.68)), and CsA (SMD, -1.7 (95% CI -3 to -0.49)) were significantly superior than the CON group. As for adverse effects (AEs), infections, nausea, emesia, myelosuppression, and glucose intolerance were the collective adverse events for most immunosuppressants. Conclusion: This study indicates that TAC + MMF performed the best in terms of TR, and TAC shows the best effectiveness on 24-h UTP compared with other regimens. On the contrary, there seems to be little advantage on STE alone, LEF, AZA, and MZB in treating patients with IMN compared with CON. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021287013].

Project description:BackgroundImmunosuppressive agents in general are shown to prevent renal progression and all-cause mortality in idiopathic membranous nephropathy (IMN) patients with nephrotic syndrome. However, the efficacy and safety of different immunosuppressive treatments have not been systematic assessed and compared. A network meta-analysis was performed to compare different immunosuppressive treatment in IMN.MethodsCochrane library, MEDLINE, EMBASE and trial register system were searched for randomized controlled trials reporting the treatments for IMN to May 3, 2016. Composite endpoint of mortality or end-stage kidney disease (ESKD), complete or partial proteinuria remission and withdrawal because of treatment adverse events were compared combing direct and indirect comparison using network meta-analysis. Ranking different immunosuppressive treatments in the outcomes were analyzed by using surface under the cumulative ranking curve (SUCRA).ResultsTotal 36 randomized controlled trials (n = 2018) covering 11 kinds of treatments were included. Compared with non-immunosuppressive treatment, only cyclophosphamide (CTX) and chlorambucil significantly reduced the risk of composite outcome of mortality or ESKD while combining the direct and indirect comparison (OR = 0.31, 95%CI: 0.12-0.81 and OR = 0.33, 95%CI: 0.12-0.92). CTX increased the composite outcome of complete remission (CR) or partial remission (PR) (OR = 4.29, 95%CI: 2.30-8.00) but chlorambucil did not (OR = 1.58, 95%CI: 0.80-3.12) as compared with non-immunosuppressive treatment. Chlorambucil also significantly increased the withdrawal risk (OR = 3.34, 95%CI: 1.37-8.17) as compared to CTX. Both tacrolimus (OR = 3.10, 95%CI: 1.36-7.09) and cyclosporine (CsA) (OR = 2.81, 95%CI: 1.08-7.32) also significantly increased the rate of CR or PR as compared with non-immunosuppressive treatment (without significant difference as compared with CTX), while ranking results showed that cyclosporine or tacrolimus was with less possibility of drug withdrawal as compared to CTX.ConclusionsCyclophosphamide and chlorambucil reduce risk of ESKD or death in IMN with nephrotic range proteinuria, but carry substantial toxicity that may be lower for cyclophosphamide. Tacrolimus and cyclosporine increase the possibility of proteinuria remission with less drug withdrawal, but the effects on kidney failure remain uncertain.

Project description:BackgroundThis study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective.MethodsTo estimate the cost-effectiveness of four regimens namely cyclophosphamide, cyclosporine, rituximab and tacrolimus-rituximab in treatment of IMN recommended by the updated Kidney Disease: Improving Global Outcomes (KDIGO) guideline 2021, a Markov model with five discrete states (active disease, remission, dialysis, kidney transplant and death) based on IMN patients aged 50 or above over a 30-years time horizon was constructed. Total costs were imputed from the Chinese healthcare system perspective, and health outcomes were converted into quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was used to describe the results. The willingness-to-pay (WTP) threshold was set at $12,044 (China's 2021 Gross Domestic Product per capita). Sensitivity analyses were performed to test the uncertainties of the results.ResultCompared with cyclophosphamide, both cyclosporine (incremental cost $28,337.09, incremental QALY-1.63) and tacrolimus-rituximab (incremental cost $28,324.13, incremental QALY -0.46) were considered at strictly dominated for their negative values in QALYs, and the ICER value of rituximab was positive (incremental cost $9,162.19, incremental QALY 0.44). Since the ICER of rituximab exceeds the pre-determined threshold, cyclophosphamide was likely to be the best choice for the treatment of IMN within the acceptable threshold range. The results of the sensitivity analysis revealed that the model outcome was mostly affected by the probability of remission in rituximab. In a probabilistic sensitivity analysis, cyclophosphamide had 62.4% probability of being cost-effective compared with other regimens when the WTP was $12,044 per QALY. When WTP exceeded $18,300, rituximab was more cost-effective than cyclophosphamide.ConclusionCompared with cyclosporine, rituximab and tacrolimus-rituximab, our model results indicated that cyclophosphamide represented the most cost-effective regimen for patients with progressive IMN in China.

Project description:Background: The efficacy and safety of immunosuppressive monotherapy agents were evaluated for immunoglobulin A nephropathy (IgAN) using a network meta-analysis approach. Methods: Randomized controlled trials (RCTs) published prior to October 1, 2019, using immunosuppressive agents for treating IgAN, were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science databases. Relative risks (RRs) or standard mean differences with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes were clinical remission, end-stage renal disease (ESRD), and serious adverse events (SAEs). The secondary outcomes were urinary protein excretion and serum creatinine. Results: Twenty-five RCTs with 2,005 participants were deemed eligible. Six medications were evaluated: corticosteroids, mycophenolate mofetil (MMF), tacrolimus (TAC), cyclosporine, leflunomide, and hydroxychloroquine (HCQ). Steroids (RR 1.50, 95% CI 1.17-1.93), MMF (RR 2.05, 95% CI 1.15-3.65), TAC (RR 3.67, 95% CI 1.06-12.63), and HCQ (RR 3.25, 95% CI 1.05-10.09) significantly improved clinical remission rates compared to supportive care alone. Only steroids reduced the risk of ESRD (RR 0.35, 95% CI 0.12-0.98); however, there were significantly more SAEs than in the control group (RR 2.90, 95% CI 1.37-6.13). No significantly different effects in serum creatinine levels were found among the therapies. MMF showed no significant improvement in remission when excluding studies with a follow-up of fewer than 2 years in the sensitivity analysis (RR 1.41, 95% CI 0.40-4.92). The effect of TAC in the decrease of proteinuria was reversed after discontinuing medication for 3 months; the long-term effects of HCQ could not be evaluated due to the short follow-up duration. Conclusion: Corticosteroids might induce remission and increase renal survival in IgAN; however, adverse reactions should be taken into consideration. MMF, TAC, and HCQ might improve the remission of proteinuria when treating IgAN, but showed no superiority compared to steroids, and the long-term effects require further study.

Dataset Information

Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis.

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Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis.

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