tacrolimus and Glomerulonephritis--Membranous

Numerous studies have demonstrated the efficiency of tacrolimus + rituximab and rituximab in idiopathic membranous nephropathy (IMN). But optimal dosages of rituximab for IMN are still controversial. This network meta-analysis (NMA) was conducted to compare the efficacy of different rituximab dosages and other main treatments in IMN treatment.. Randomized controlled trials (RCTs) and observational studies analyzing nine therapeutic regimens for IMN were included from some databases. Network comparisons were performed to analyze the rates of total remission (TR) and relapse rate. The surface under the cumulative ranking area (SUCRA) was calculated to rank interventions.. Twelve RCTs and 12 observational studies involving 1724 patients were pooled for comparison of 9 interventions. This NMA demonstrated steroids + tacrolimus was ranked first in the aspect of total remission at 6 months (92%) and 12 months (81.3%). The total remission rate associated with tacrolimus + rituximab increased rapidly between the sixth (SUCRA 22.5%) and the twelfth month (SUCRA 63.9%). Tacrolimus and cyclosporine A were associated with higher total remission at 6 months (78.8% and 65.4%, separately) and decreased at 12 months (58.1 and 34.9%, separately). Steroids + cyclophosphamide, rituximab (Heavy dose) and rituximab (Low dose) had stable remission rates at 6 (63.7%, 46.6%, and 19.4%) and 12 months (SUCRA 66.9%, 39.6%, and 28.8%). Tacrolimus and cyclosporine A were associated with a significantly higher risk of relapse than that with steroids + cyclophosphamide, rituximab (Heavy dose), and rituximab (Low dose).. For IMN in adults, steroids + tacrolimus was ranked first in the aspect of total remission, followed by steroids + cyclophosphamide and steroids + cyclosporine A. The TR associated with rituximab (Heavy and Low dosage) at 12 months was higher than that at 6 months. And rituximab (Heavy dose) achieves a higher rate of total remission than that of rituximab (Low dose).

Topics: Adult; Cyclophosphamide; Cyclosporine; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Network Meta-Analysis; Rituximab; Tacrolimus; Treatment Outcome

To explore the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in patients with idiopathic membranous nephropathy (IMN).. A literature search was performed using Embase, Cochrane Library and PubMed from inception through May 31, 2021. All randomized controlled trials (RCTs) exploring the efficacy and safety of TAC combined with corticosteroids in IMN patients were included based on the inclusion and exclusion criteria. Data analyses were conducted using RevMan software (version 5.4).. Seven RCTs involving 520 patients were included in this meta-analysis. Compared with control treatment, TAC combined with corticosteroids could significantly increase the complete remission (CR) rate, total remission (TR) rate, and serum albumin levels, as well as decrease the proteinuria levels within 6-month treatment, but the advantage did not persist to 12-month treatment. After 18-month treatment, the effect of TAC combined with corticosteroids on increasing CR rate, TR rate, and serum albumin levels was significantly worse than control treatment. The mean time to remission in TAC combined corticosteroids group was significantly shorter than that in the control group. The relapse rate, no response rate, change in estimate of the glomerular filtration rate (eGFR), and overall incidence of adverse reactions showed no significant difference between TAC combined with corticosteroids group and control group. However, TAC combined with corticosteroids did have a higher risk of hand tremor, nephrotoxicity, and glucose intolerance than control treatment.. TAC combined with corticosteroids has a significant therapeutic effect for IMN patients within 1-year treatment, especially in the first 6 months. However, in the longer-term treatment, TAC combined with corticosteroids does not have an advantage. TAC combined with corticosteroids has a higher risk of hand tremor, nephrotoxicity, and glucose intolerance. More high-quality studies are needed to further verify the long-term efficacy and safety of TAC combined with glucocorticoids in IMN patients.

Topics: Adrenal Cortex Hormones; Drug Therapy, Combination; Glomerulonephritis, Membranous; Glucose Intolerance; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Serum Albumin; Tacrolimus; Treatment Outcome; Tremor

Numerous studies have demonstrated that the efficacy of drugs differs in idiopathic membranous nephropathy (IMN) patients with moderate or high proteinuria. However, there is no systematic comparison confirming it. This network meta-analysis (NMA) was performed to respectively compare the efficacy of ten IMN treatments in patients with moderate and high proteinuria and compare the risk of adverse events with 10 IMN regimens.. Randomized controlled trials (RCTs) and observational studies analyzing the main therapeutic regimens for IMN were included from some databases. Network comparisons were performed to analyze the rates of total remission (TR), bone marrow suppression, and gastrointestinal symptoms. The surface under the cumulative ranking area (SUCRA) was calculated to rank interventions.. Seventeen RCTs and eight observational studies involving 1778 patients were pooled for comparison of ten interventions. Steroid + tacrolimus (TAC) showed the highest probabilities of TR whether patients had severe proteinuria or not (SUCRA 89.5% and 88.9%, separately). Rituximab (RTX) was more beneficial for TR on patients with proteinuria <8 g/d (SUCRA 66.0%) and was associated with a lower risk of bone marrow suppression and gastrointestinal symptoms (SUCRA 21.7% and 21.4%, separately). TAC + RTX and steroids + cyclophosphamide induced the highest rates of bone marrow suppression (SUCRA 90.6% and 88.3%, separately) and gastrointestinal symptoms (SUCRA 86.0% and 72.1%, separately).. Steroids + TAC showed significant efficacy in patients with all degrees of proteinuria, while RTX was more effective in patients with moderate proteinuria and was safer in bone marrow suppression and gastrointestinal symptoms.

Topics: Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Network Meta-Analysis; Proteinuria; Rituximab; Steroids; Tacrolimus

The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus TAC-corticosteroid combination therapy in idiopathic membranous nephropathy (IMN) patients.. Databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from inception to January 10, 2021. Eligible studies comparing TAC monotherapy and TAC-corticosteroid combination therapy in IMN patients were included. Data were analysed using Review Manager Version 5.3.. Seven studies were included in the meta-analysis. One randomized controlled trial and six cohort studies involving 372 patients were identified. Compared with TAC monotherapy, TAC-corticosteroid had a higher total remission at the sixth month (odd ratio (OR) 0.49, 95% confidence interval (CI) 0.31-0.78, P < .01). The two therapy regimens had similar complete remission rates (OR 0.79, 95% CI 0.43-1.48, P = .47) at the sixth month and similar relapse rates (OR 1.44, 95% CI 0.70-2.92, P = .32). TAC-corticosteroid combination therapy had a higher incidence of infection (OR 0.38, 95% CI 0.18-0.81, P = .01). The two therapy regimens had similar incidences of gastrointestinal symptoms (OR 0.96, 95% CI 0.34-2.70, P = .93), abnormal aminotransferase (OR 0.90, 95% CI 0.34-2.38, P = .84), and glucose intolerance (OR 0.58, 95% CI 0.32-1.07, P = .08).. TAC-corticosteroid combination therapy had a higher total remission rate at the sixth month but had a higher incidence of infection than TAC monotherapy in the treatment of IMN. The two therapeutic regimens had similar relapse rates.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Recurrence; Tacrolimus; Treatment Outcome

The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus cyclophosphamide (CTX)-corticosteroid combination therapy in idiopathic membranous nephropathy (IMN) patients.. Databases including the PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from inception to October 20, 2020. Eligible studies comparing TAC monotherapy and CTX-corticosteroid combination therapy in IMN patients were included. Data were analyzed using Review Manager Version 5.3.. Nine studies were included in the meta-analysis. One randomized controlled trial and eight cohort studies involving 442 patients were identified. Compared with CTX-corticosteroid combination therapy for IMN, TAC monotherapy had higher complete remission (CR) at month 6 (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.35-3.50, P < .01). The 2 therapeutic regimens had similar partial remission (OR 0.69, 95% CI 0.45-1.04, P = .08), total remission (OR 1.38, 95% CI 0.85-2.23, P = 0.19) at month 6, and similar CR (OR 1.64, 95% CI 0.84-3.19, P = .15), partial remission (OR 0.71, 95% CI 0.37-1.38, P = 0.31), and total remission (OR 1.29, 95% CI 0.55-3.01, P = .56) after 1 year. The relapse rate of the TAC group was higher than that of the CTX group, but the difference was not statistically significant (OR 1.85, 95% CI 0.75-4.53, P = .18). There was no difference between the 2 therapeutic regimens concerning glucose intolerance (OR 1.15, 95% CI 0.61-2.14, P = .67), acute renal failure (OR 1.14, 95% CI 0.39-3.33, P = .81), or tremors (OR 4.39, 95% CI 0.75-25.67, P = .10). Incidences of gastrointestinal symptoms (OR 0.29, 95% CI 0.10-0.79, P = .02), infection (OR 0.18, 95% CI 0.08-0.39, P < 0.01), leukopenia (OR 0.14, 95% CI 0.04-0.51, P < .01), and abnormal aminotransferase (OR 0.31, 95% CI 0.13-0.77, P = .01) in the TAC group were all lower than those in the CTX group. Subgroup analysis showed that there was no significant difference between the TAC group and the CTX combined with corticosteroid 0.8 to 1 mg/kg/day group concerning CR at month 6 (P > .05). There was no significant difference between the TAC group and the CTX combined with corticosteroid 0.5 mg/kg/day group concerning abnormal aminotransferase (P > .05).. TAC monotherapy is comparable to CTX-corticosteroid combination therapy for renal remission in IMN patients. TAC monotherapy had a higher CR in the early stage and had fewer drug-related adverse effects. The relapse rate of TAC monotherapy was higher than that of CTX-corticosteroid combination therapy, but the difference was not significant.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus

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.. Systematic review and network meta-analysis.. 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.. 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.. Two reviewers independently screened articles, extracted data and assessed study quality. Standard pairwise meta-analysis was performed using DerSimonian-Laird random-effects model.. 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.. 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.. CRD42018094228.

Topics: Adult; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Network Meta-Analysis; Randomized Controlled Trials as Topic; Tacrolimus; Tripterygium

Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN.. Randomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions.. A total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34-0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs.. CSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN. PROSPERO registration: CRD42018104849.

Topics: China; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk; Tacrolimus

As one of the therapeutic drugs for idiopathic membranous nephropathy (IMN), tacrolimus (TAC) has not been fully vindicated for its efficacy and tolerability. A meta-analysis was performed to detect the efficacy and safety of TAC plus glucocorticoid vs cyclophosphamide (CTX) plus glucocorticoid in therapy of patients with IMN.. A literature search with a pre-defined search strategy was conducted using English databases (PubMed, EMBASE, ClinicalKey and the Cochrane Library) and Chinese databases (China National Knowledge International, Wanfang, Chinese Scientific Journal Database (VIP)) from inception to Nov 19, 2018. Any high-quality randomized controlled trials (RCTs) comparing the effectiveness or safety of TAC with CTX in IMN patients were included. Data were extracted by two authors independently and analyzed using RevMan 5.3.. Four randomized controlled studies were included. In this analysis, we did not find that the statistically significant difference between TAC and CTX groups on 6-month and 12-month treatment complete remission (CR) was evident (6-month: OR=1.53, 95% CI: 0.85-2.76,. TAC treatment could get high value of TR and had low value of proteinuria level when compared with those in CTX on 6-month treatment in therapy of patients with IMN.

Topics: Cyclophosphamide; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus

Objective To compare the efficacy and safety of tacrolimus with those of cyclosporine in treating idiopathic membranous nephropathy (IMN) via network meta-analysis. Methods Databases including PubMed,Embase,CENTRAL (Cochrane),Wanfang Database,CNKI,and VIP citation database were searched for relevant studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Package Meta 4.5.0 and Gemtc 0.8.1 in R 3.3.1 were used to analyze the included studies. Results In this network meta-analysis,the complete remission rate (RR=0.98,95% CI:0.70-1.40)and the total remission rate (RR=1.00,95% CI:0.90-1.20)of idiopathic membranous nephropathy did not differ significantly between IMN patients treated with cyclosporine A or tacrolimusand,nor did the incidences of hepatic dysfunction(RR=1.40,95% CI:0.52-4.00),infection(RR=0.75,95% CI:0.18-3.10),or gastrointestinal syndrome(RR=2.1,95% CI:0.36-28.00). Conclusion Cyclosporine A seems to have similar effectiveness and safety to tacrolimus in treating IMN.. 目的 采用网状Meta分析的方法对他克莫司与环孢素A治疗特发性膜性肾病(IMN)的疗效与安全性进行对比分析。方法 依据PRISMA,检索PubMed、Embase、Cochrane CENTRAL、万方数据库、中国知网、维普数据库,并根据以往相关综述和荟萃分析所引用的参考文献进一步检索随机对照试验。采用R3.3.1软件Meta 4.5.0包和Gemtc 0.8.1包对纳入的研究文献进行网状荟萃分析。结果 与他克莫司相比,环孢素A在治疗成人IMN时的完全缓解率(

Topics: Cyclosporine; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Network Meta-Analysis; Tacrolimus

Amelioration of podocyte injury, which can lead to podocyte detachment, is the target of therapeutic intervention in glomerular diseases. Since podocytes are terminally differentiated cells with little or no proliferative ability, their loss results in permanent glomerular dysfunction. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression, which indirectly ameliorates podocyte injury by interrupting the input of immunological stress. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data now suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. Indeed, the therapeutic efficacy of immunomodulatory agents is, at least in part, derived by the direct action on podocytes. In this review, we discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance.

Topics: Abatacept; Adjuvants, Immunologic; Calcineurin Inhibitors; Everolimus; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Levamisole; Mycophenolic Acid; Nephrosis, Lipoid; Nephrotic Syndrome; Podocytes; Ribonucleosides; Rituximab; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Immunosuppressive 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.. Cochrane 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).. Total 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.. Cyclophosphamide 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.

Topics: Chlorambucil; Cyclophosphamide; Cyclosporine; Drug Tolerance; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Randomized Controlled Trials as Topic; Tacrolimus

The objective of this systematic review was to compare the efficacy and safety of tacrolimus with cyclophosphamide in primary membranous nephropathy (PMN) patients.. We conducted a literature search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CCRCT). Any study that compared the efficacy or safety between tacrolimus and cyclophosphamide in the adult PMN patients was included.. We included four randomized controlled trials and two prospective cohort studies with 389 PMN patients. The pooled results using the Dersimonian and Laird method showed that renal remission rates at the longest follow-up periods were not significantly different between the tacrolimus and cyclophosphamide groups (overall remission, six trials, n = 389, relative risk [RR] 0.994 [95% confidence interval [CI] 0.768-1.286); complete remission, six trials, n = 389, RR 1.256 [95% CI 0.733-2.150]). Further analyses found that tacrolimus was comparable with cyclophosphamide for inducing renal remission within 1 year but inferior to cyclophosphamide after 1-year follow-up. It should be noted that only two studies reported the outcomes after 1-year follow-up, which might be considered as weak evidence. The rates of relapse and the drop-outs due to adverse effects were not significantly different (relapse, six trials, n = 389, RR 2.244 [95% CI 0.892-5.644]; drop-outs, six trials, n = 389, RR 1.330 [95% CI 0.412-4.291]). However, the cyclophosphamide group had a significantly higher risk of leukopenia than the tacrolimus group (four trials, n = 216, RR 0.203 [95% CI 0.045-0.916]), whereas the rates of tremor were significantly higher in the tacrolimus group than in the cyclophosphamide group (three trials, n = 202, RR 8.939 [95% CI 1.694-47.173]).. The quality and short follow-up durations of the studies limited the reliability of our conclusions.. Tacrolimus was comparable with cyclophosphamide for inducing renal remission of PMN patients within 1 year, but the long-term effects need to be investigated. The cyclophosphamide group had a significantly higher risk of leukopenia, whereas the tacrolimus group had significantly higher rates of tremor. These conclusions need to be further verified.

Topics: Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Tacrolimus

The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN) were compared in Chinese adult patients using a meta- analysis of the available literatures. Randomized controlled clinical trials (RCTs) of the treatment of primary IMN with TAC or CTX combined with corticosteroids in the English databases PubMed, Embase and Cochrane, as well as Chinese databases, were searched. Qualified studies were subjected to quality assessment and meta-analysis. A total of 8 RCTs, including 359 Chinese patients, were included in the meta-analysis. The complete remission rate and overall remission rate in the TAC treatment group after 6 months of treatment were higher than those in the CTX treatment group. No significant difference in remission rate was found after 12 months of treatment. There was no significant difference in the adverse reaction between the two groups at the 6th or 12th months. TAC-based treatment was associated with a faster response than CTX at the 6th month, but there was no significant difference between the two groups at 12th month in Chinese adults. Further study is needed to evaluate the long-term efficacy and safety of this treatment regimen.

Topics: Adult; Asian People; Cyclophosphamide; Female; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Patient Safety; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) are still controversial. Recent studies showed tacrolimus is effective in the treatment of IMN. To evaluate the efficacy and safety of tacrolimus (TAC) for IMN, we conducted a meta-analysis of published medical literatures.. Studies addressing the effect of tacrolimus in IMN were searched on PUBMED, EMBASE, The Cochrane Library, and ClinicalTrials.gov (March 2013). Trials comparing tacrolimus with corticosteroid versus control group (cyclophosphamide with corticosteroid) were included. The quality of the studies was assessed using Jadad method. Statistical analyses were performed using Review Manager 5.2 and the results were summarized by calculating the risk ratio (RR) for dichotomous data or the mean difference (MD) for continuous data with 95% confident interval (CI).. A total of four studies (259 patients) were included. It was shown that therapy with tacrolimus plus corticosteroid had a higher complete remission rate compared to therapy with cyclophosplamide plus corticosteroid (RR = 1.53, 95% CI: 1.05-2.24, P < 0.05), but not significant on total remission, partial remission and adverse effects. Also, no significant alterations were observed in proteinuria and serum albumin level between the two groups. During the entire follow-up period, serum creatinine level remained stable in both groups without = 50% increase in its level.. TAC is more effective than cyclophosphamide (CTX) by achieving complete remission in patients with IMN. Multi-ethnic RCTs are needed to evaluate its long-term efficacy and safety.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Tacrolimus

Idiopathic membranous nephropathy (IMN) is the most common pathological type for nephrotic syndrome in adults in western countries and China. The benefits and harms of immunosuppressive treatment in IMN remain controversial.. To assess the efficacy and safety of different immunosuppressive agents in the treatment of nephrotic syndrome caused by IMN.. PubMed, EMBASE, Cochrane Library and wanfang, weipu, qinghuatongfang, were searched for relevant studies published before December 2011. Reference lists of nephrology textbooks, review articles were checked. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager.. 17 studies were included, involving 696 patients. Calcineurin inhibitors had a better effect when compared to alkylating agents, on complete remission (RR 1.61, 95% CI 1.13, to 2.30 P = 0.008), partial or complete remission (effective) (CR/PR, RR 1.29, 95% CI 1.09 to 1.52 P = 0.003), and fewer side effects. Among calcineurin inhibitors, tacrolimus (TAC) was shown statistical significance in inducing more remissions. When compared to cyclophosphamide (CTX), leflunomide (LET) showed no beneficial effect, mycophenolate mofetil (MMF) showed significant beneficial on effectiveness (CR/PR, RR: 1.41, 95% CI 1.16 to 1.72 P = 0.0006) but not significant on complete remission (CR, RR: 1.38, 95% CI 0.89 to 2.13 P = 0.15).. This analysis based on Chinese adults and short duration RCTs suggested calcineurin inhibitors, especially TAC, were more effective in proteinuria reduction in IMN with acceptable side effects. Long duration RCTs were needed to confirm the long-term effects of those agents in nephrotic IMN.

Topics: Adult; Alkylating Agents; Calcineurin Inhibitors; China; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Cyclosporine; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Tacrolimus

Topics: Antineoplastic Combined Chemotherapy Protocols; Azathioprine; Calcineurin Inhibitors; Drug Therapy, Combination; Fluorouracil; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Mitomycin; Prognosis; Ribonucleosides; Semustine; Tacrolimus

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Rituximab; Tacrolimus; Treatment Outcome

Idiopathic membranous nephropathy (IMN) remains the leading cause of adult nephrotic syndrome. Immunosuppressive therapy with cyclophosphamide (CTX) is often successful in reducing proteinuria, but its use is associated with severe side effects. Tacrolimus (TAC) is effective in achieving complete remission (CR) in patients with IMN. However, whether it is as effective as CTX in inducing and maintaining complete or partial remission in these patients is unknown. This trial aims to test TAC monotherapy for its non-inferiority to CTX in inducing long-term remission of proteinuria.. Patients with biopsy-proven IMN with nephrotic syndrome will be randomized into a 12-month treatment period with oral TAC of 0.05-0.1 mg/kg/day for 6 months or with CTX + glucocorticoid. The efficacy of the treatment will be assessed by the remission status (based on changes in proteinuria) and relapse rate.. This study will test whether treatment with TAC monotherapy is superior to CTX with glucocorticoid in inducing long-term remission of proteinuria in patients with adult IMN. The role of serum anti-PLA2R antibodies in the early assessment of the response to therapy using different therapeutic regimens will also be clarified.. ClinicalTrials.gov ChiCTR1800016140. Registered 12 June 2017. http://www.chictr.org.cn.

Topics: Adolescent; Adult; Aged; Autoantibodies; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Phospholipase A2; Tacrolimus; Young Adult

Tacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate.. Forty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function.. 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment.. Addition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN.. This trial is registered with EudraCTN2008-001009-41 . Trial registration date 2008-10-08.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Recurrence; Remission Induction; Tacrolimus; Young Adult

The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids.. Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p > .05). Proteinuria (based on 24 h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase.. TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short-term efficiency and patient tolerance are both acceptable.

Topics: Adult; Cyclophosphamide; Diabetes Mellitus; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Glucocorticoids; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome

There have been very few studies comparing cyclophosphamide (CTX) and calcineurin inhibitor based regimens in the management of non-immunosuppressive symptomatic therapy (NIST) resistant idiopathic membranous nephropathy (IMN). The present study was aimed at comparing the efficacy and safety of tacrolimus (TAC)/steroids with cyclical CTX/steroids (Modified Ponticelli regimen (MPR)) in patients with IMN.. Idiopathic membranous nephropathy patients (n = 70) with persistent nephrotic syndrome after at least 6 months of antiproteinuric therapy or with complications of nephrotic syndrome were equally randomized to receive TAC with oral prednisolone (TAC*) or MPR. Antibodies against m-type phospholipase A2 receptor (PLA2R Ab) were tested for at baseline and, at 6 and 12 months after the start of therapy. The primary end point was achievement of remission and secondary objectives were adverse effects and estimated glomerular filtration rate in both the study groups.. Intention-to-treat analysis showed that remissions at the end of 6 (74% with TAC* vs. 60% with MPR; P = 0.30) and 12 months (71% with TAC* vs. 77% with MPR; P = 0.78) were comparable. PLA2R Ab titres at 6/12 months correlated with urine protein (r 0.54/0.58) and serum albumin (r -0.49/-0.53) at the end of therapy. Patients on CTX had a significantly higher risk of amenorrhea and while those on TAC had a greater risk of reversible nephrotoxicity.. In NIST refractory IMN, both TAC* and MPR are comparable, but with different adverse effect profile. PLA2 R Ab has a very good association with proteinuria, and should be regularly monitored on clinical follow-up.

Topics: Adrenal Cortex Hormones; Adult; Autoantibodies; Biomarkers; Calcineurin Inhibitors; Cyclophosphamide; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; India; Intention to Treat Analysis; Male; Methylprednisolone; Middle Aged; Predictive Value of Tests; Receptors, Phospholipase A2; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Immunosuppressive therapy plays an important role in patients with high-risk idiopathic membranous nephropathy (IMN), but the therapeutic modality is still controversial.. Corticosteroid combined with oral tacrolimus (TAC, target trough blood concentration of 4-8 ng/mL), intravenous cyclophosphamide (CYC, 750 mg/m(2)/mo, or oral mycophenolate mofetil (MMF, 1.5-2.0 g/d) were randomly administered for 9 months to 90 patients with IMN proved with renal biopsy with severe proteinuria (>8 g/d).. Eighty-six of the 90 patients completed the study. The total remission (TR) rates in the TAC group were significantly higher than those in the CYC group at 1 and 2 months (p < 0.01) and the MMF group at 1-4 months (p < 0.01). The TR rates were 83.3%, 73.3%, and 70.0% in the TAC, CYC, and MMF groups at 9 months (p = 0.457), and there were no significant differences between the three groups from 5 to 9 months. Furthermore, TAC reduced proteinuria and ameliorated hypoalbuminemia more quickly and effectively than CYC and MMF. We observed no severe adverse events in the three groups.. Tacrolimus combined with corticosteroid had tolerable adverse effects and induced the remission of IMN more effectively and more rapidly. This is the first prospective randomized cohort study to compare three different therapies in patients at high risk for IMN. It provides strong evidence for choosing optimal treatment for patients with IMN. The long-term efficacy of this treatment strategy should be investigated further in future studies.

Topics: Adrenal Cortex Hormones; Adult; China; Cyclophosphamide; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Proteinuria; Remission Induction; Tacrolimus; Treatment Outcome

Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome among adults. Considering the natural course of IMN, when to treat and with which immunosuppressive treatment need to be carefully considered in such patients. A combination of tripterygium wilfordii multiglycosides (TWG) and prednisone may be an effective option for treating patients with IMN.. In this prospective cohort study, we enrolled patients with biopsy-proven IMN at our kidney centre. One cohort received TWG combined with prednisone, whereas another cohort received tacrolimus (TAC) combined with prednisone, for 36 weeks. The primary outcome was the remission rate, whereas the secondary outcomes included the time to remission, relapse rate, changes in serum albumin levels and daily urinary protein levels, estimated glomerular filtration rate, and adverse events.. A total of 53 patients with IMN met the criteria for enrollment, and all patients completed the therapy. At the end of the 36-week therapy, remission (either partial remission [PR] or complete remission [CR]) was observed in 20 patients (86.9 %) receiving TWG and in 27 patients (90.0 %) receiving TAC (p > 0.05), whereas CR was noted in 12 patients (52.2 %) receiving TWG and 14 patients (46.7 %) receiving TAC (p > 0.05). The probability of remission was similar for both the TWG and TAC groups (p > 0.05, by log-bank test). The mean time for achieving remission was 11.8 ± 12.5 weeks in the TWG group and 8.5 ± 9.1 weeks in the TAC group (p > 0.05).. The combination of TWG and predisone is an effective and safe therapy for IMN.

Topics: Adult; Cohort Studies; Drugs, Chinese Herbal; Female; Glomerulonephritis, Membranous; Glycosides; Humans; Immunosuppressive Agents; Male; Middle Aged; Phytotherapy; Prospective Studies; Tacrolimus; Treatment Outcome; Tripterygium

Tacrolimus is an effective (but relatively expensive) immunosuppressant that is used widely in patients with membranous nephropathy. To reduce the tacrolimus dose while maintaining an equivalent therapeutic effect, we studied the clinical efficacy and pharmacoeconomic impact of co-administration of Wuzhi capsules (WZC that protects against damage to liver cells) and tacrolimus.. Sixty patients with membranous nephropathy were divided randomly into two groups: experimental (tacrolimus + WZC + corticosteroids) and control (tacrolimus + corticosteroids). Each group received treatments continuously for >6 months. Liver function; renal function; and whole-blood concentrations of tacrolimus, sugars, lipids, as well as 24-h urinary protein levels were used in the clinical evaluation. The cost of drugs was calculated, and the pharmacoeconomic cost-effectiveness analyses were carried out to compare indices between the two groups.. Doses and costs of tacrolimus differed significantly between experimental and control groups (p < 0.01 or p < 0.05). Costs in the experimental group were 13,702.62 ± 1,458.6 CNY (2,194.10 ± 233.56 USD) and those in the control group were 17,796.87 ± 2,469.27 CNY (2,849.69 ± 395.39 USD), with clinical efficacy of 93.3 and 90.0 %, respectively. The cost-effectiveness ratios were 146.86 ± 15.63 and 197.73 ± 27.44, respectively. Compared with the experimental group, the control group showed an incremental cost-effectiveness ratio of 1,240.68 ± 306.25 CNY (198.66 ± 49.04 USD), whereas remission between the two groups was similar.. Co-administration of WZCs and tacrolimus can reduce the dose of tacrolimus and decrease the costs incurred by patients within the same therapeutic window to that seen for treatment with tacrolimus alone.

Topics: Adrenal Cortex Hormones; Adult; Biopsy; Capsules; Drug Therapy, Combination; Drugs, Chinese Herbal; Economics, Pharmaceutical; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Function Tests; Male; Tacrolimus; Treatment Outcome

Tacrolimus has been used for idiopathic membranous nephropathy (IMN) therapy, but most patients who achieved remission showed a high relapse rate when tacrolimus was withdrawn after 6-12 months of therapy. We proposed that a prolonged therapeutic course should help reduce the relapse rate.. A total of 42 patients with nephrotic syndrome caused by IMN were randomly divided into short-term (n = 20) and long-term (n = 22) groups. All patients received initial treatment with tacrolimus and prednisone for 6 months, and afterward only the long-term patient group was tapered with low-dose tacrolimus until 24 months.. Over 85% of the patients achieved proteinuria reduction, serum albumin improvement and serum lipid recovery; the probability of remission in both groups was over 80% at 6 months. The remission rate was steady at over 80% after 12 and 24 months in the long-term group, but only 50 and 45%, respectively, in the short-term group. Nine patients (45%) relapsed in the short-term group after tacrolimus withdrawal, while not a single patient suffered recurrence in the long-term group. The concentration of tacrolimus remained similar between the two groups at 5-8 ng/ml during the initial 6 months, and was significantly decreased at 12 months compared to 6 months (p < 0.05), along with reduction of oral administration in the long-term group.. Combined therapy of tacrolimus with prednisone can relieve IMN significantly; prolonged tacrolimus treatment at a low blood concentration can alleviate the illness persistently, with a low recurrence rate and gratifying safety.

Topics: Adult; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Proteinuria; Serum Albumin; Tacrolimus; Treatment Outcome

Although idiopathic membranous nephropathy (IMN) is the most common cause of adult-onset nephrotic syndrome, the management of IMN remains controversial. The aim of this prospective study was to compare the efficacy and drug safety of tacrolimus with that of cyclophosphamide (CTX; control group) in IMN patients receiving corticosteroid therapy. A total of 100 IMN patients with nephrotic syndrome were randomly assigned to receive a combination of corticosteroid therapy and either CTX or tacrolimus. During a follow-up period of at least 18 months, the remission rate after 2 months in the tacrolimus group was 65.1%, which was higher than that of the CTX group (44.2%) (p = 0.02). The mean time to partial or complete remission was 2.20 months in the tacrolimus group and 3.92 months in the CTX group (p < 0.001). We also found significantly greater improvements in the serum albumin levels in the tacrolimus group compared with the CTX group at the 2-month (p = 0.003) and 3-month time points (p = 0.01). The serum creatinine levels remained stable in both groups. Although remission was quicker and more common in the tacrolimus group (compared with the CTX group) before 3 months, there was no superiority of tacrolimus after 6 months. Glucose intolerance, urinary tract infections, and pneumonia were the major side effects observed in this study. All of the side effects were mild and controlled, and there were fewer side effects in the tacrolimus group compared with the CTX group, indicating a better treatment tolerance in the tacrolimus group.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Cyclophosphamide; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus

Idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults, is usually treated with corticosteroids in combination with cyclophosphamide or cyclosporine. A recent placebo-controlled study suggested that tacrolimus monotherapy was effective in IMN. However, the effectiveness of tacrolimus versus classic regimen and its potential nephrotoxicity remain inconclusive. This study evaluated the efficacy and safety of tacrolimus plus prednisone in patients with nephrotic IMN.. Seventy-three patients with nephrotic IMN were recruited in this multicenter randomized controlled trial, 39 receiving tacrolimus and prednisone, while 34 receiving cyclophosphamide and prednisone. Tacrolimus was given at 0.1 mg/kg/d initially and adjusted to a blood trough level at 5 to 10 ng/mL for 6 months and then reduced to 2 to 5 ng/mL in the subsequent 3 months.. Intention-to-treat analysis suggested that the remission rate at the end of the sixth month was significantly higher in tacrolimus group than that in cyclophosphamide group (85% versus 65%, P < 0.05). The decrease of proteinuria was significantly greater in tacrolimus group. At the end of the 12th month, the remission rates were comparable between these 2 groups. Patients treated with tacrolimus were more likely to develop glucose intolerance (or diabetes mellitus), infection, and hypertension. No obvious nephrotoxicity of calcineurin inhibitor was found in repeat renal biopsy.. Tacrolimus plus corticosteroids is an alternative therapeutic regimen for nephrotic IMN. The short-term efficacy might be better than cyclophosphamide plus prednisone.

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Treatment Outcome

Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.

Topics: Adult; Blood Pressure; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Treatment Outcome

Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. Its treatment is still under debate.. We report our experience in a pilot study using initially low doses of steroids and tacrolimus (Tac). After 3 months of treatment, mycophenolate mofetil (MMF) was added if the proteinuria was higher than 1 g/day.. In accordance with this standard, 21 patients entered the study. A proteinuria level lower than 1 g/day was reached at month 3 of therapy with steroids and Tac in 11 patients. These patients continued this treatment for 12 months. MMF was added in nine cases after the third month and triple therapy was maintained for 12 more months. Two patients were withdrawn because of side effects. At the end of the treatment, remission of the NS was present in 15 out of all the patients (71.4%). Remission of the NS was complete in eight (53.3%) patients and partial in seven (46.7%) others. The remaining four patients did not respond. There were no significant changes in renal function. At a mean time of 23.1 months after treatment was discontinued, 11 (73.3%) patients had relapsed.. In this trial, treatment with tacrolimus showed a good efficacy but a high relapse rate when it was discontinued.

Topics: Adrenal Cortex Hormones; Adult; Aged; Albuminuria; Biopsy; Cholesterol; Creatinine; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Tacrolimus

This study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective.. To 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.. Compared 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.. Compared 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.

Topics: China; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Cyclophosphamide; Cyclosporins; Glomerulonephritis, Membranous; Humans; Immunosuppression Therapy; Quality-Adjusted Life Years; Renal Dialysis; Rituximab; Tacrolimus

Conventional regimens for refractory idiopathic membranous nephropathy (IMN) still have limitations. Rituximab (RTX) has a good effect in the treatment of refractory IMN. However, whether RTX single or combined with immunosuppressive therapy is more effective and whether adverse events will increase are still inconclusive.. To investigate the efficacy and safety of RTX combined with low-dose tacrolimus (TAC) versus RTX alone in the treatment of refractory IMN.. A retrospective cohort study.. We retrospectively studied 91 cases of refractory IMN diagnosed between January 2018 and June 2021, all of which immunosuppressive regimens had failed. Thirty-four patients received RTX combined with TAC (RTX + TAC group), and 57 patients were treated with RTX alone (RTX group). The RTX + TAC group was given RTX 1 g once every 2 weeks, two times, and TAC 0.03 mg/kg/day orally. In the RTX group, RTX was given at the same dosage as the RTX + TAC group. Clinical data were collected at 12 months of follow-up to compare the complete and partial remission rates and the incidence of adverse reactions between the two groups.. The overall effectiveness rate of RTX + TAC in the treatment of refractory IMN was 87.14%, of which the partial and complete remission rates were 50.01% and 37.13%, respectively, and the median time to complete remission was 9 (interquartile range [IQR] 6.0, 12.0) months. The overall effectiveness rate of RTX was 65.87%, of which the partial and complete remission rates were 39.48% and 26.39%, respectively, and the median time to complete remission was 10.5 (IQR 6.0, 12.0) months. Adverse events occurred in 6 (17.65%) patients in the RTX + TAC group and in 11 (19.30%) in the RTX group (. The complete and partial remission rates of RTX combined with low-dose TAC in the treatment of refractory IMN are higher than those of RTX alone, and no significant increase in adverse events was noted.

Topics: Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Retrospective Studies; Rituximab; Tacrolimus

To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients.. A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment.. Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (. Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.

Topics: Autoantibodies; Cyclosporine; Glomerulonephritis, Membranous; Homozygote; Humans; Immunosuppressive Agents; Pharmacogenomic Testing; Receptors, Phospholipase A2; Sequence Deletion; Serum Albumin; Tacrolimus

The association between membranous nephropathy (MN) and Kimura's disease (KD) has been reported in recent years. The treatment, effect, and prognosis of KD are still unclear.. A 47-year-old KD patient developed a left axillary mass for 3 years and received surgical resection because of the lager mass in August 2016. Then he developed nephrotic syndrome 3 months later. Laboratory index revealed increased eosinophil count, decreased albumin and heavy proteinuria. Lymph node biopsy suggested KD, and renal biopsy suggested MN. He relapsed after a treatment with methylprednisolone (52 mg/d) alone and then tacrolimus (1.5 mg/12h) was added. The patient had no symptoms of relapse in the next 2 years.. The combination therapy of surgery, methylprednisolone, and immunosuppressive agents may be effective in KD with MN.

Topics: Angiolymphoid Hyperplasia with Eosinophilia; Glomerulonephritis, Membranous; Humans; Kimura Disease; Male; Middle Aged; Nephrotic Syndrome; Tacrolimus

Membranous nephropathy (MN) is the most common cause of glomerulopathy after hematopoietic cell transplantation (HCT), most often occurring in the setting of graft versus host disease (GVHD). Twenty percent of patients will fail to respond to standard therapy and may progress to end stage renal disease. Here we present the case of a pediatric patient who developed chronic oral GVHD more than one-year post-HCT, who subsequently developed nephrotic syndrome (anasarca, nephrotic range proteinuria, hypoalbuminemia) and had a renal biopsy consistent with MN. Treated with ibrutinib for her GVHD, and steroids, tacrolimus, and rituximab for her MN, she failed to achieve even partial remission of her kidney disease after 8 months. Due to steroid toxicity and 0% CD19 cells on lymphocyte subpopulation flow cytometry, the decision was made to trial plasma cell depletion therapy with daratumumab.. She received three doses of daratumumab at weeks 1, 4, and 17.. Her nephrotic syndrome resolved and her serum albumin was greater than 3.0 gm/dl by week 10. She was weaned off of both steroids and tacrolimus by week 16, at which time she had near-complete remission of her renal disease.. Daratumumab may be an important, novel therapeutic option for post-HCT MN patients who are not responsive to standard therapies.

Topics: Antibodies, Monoclonal; Child; Female; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Male; Nephrotic Syndrome; Steroids; Tacrolimus

Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we report, for the first time, a case of GS overlapping nephrotic syndrome (NS) related to PLA2R-associated membranous nephropathy (MN).. We described a male patient had a 4-year history of recurrent fatigue. Serum biochemistry revealed hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hyperreninemia, hypocalciuria, as well as nephrotic-range proteinuria, hypoalbuminemia, and elevated serum anti-phospholipase A2 receptor (PLA2R) antibody. Gene sequencing identified compound heterozygous mutations in SLC12A3 [c.536T > A(p.V179D) and c.1456G > A(p.D486N)]. The unusual association of SLTs and nephrotic-range glomerular proteinuria prompted us to perform a renal biopsy. Renal biopsy showed idiopathic MN. Due to the potential to activate the sodium-chloride co-transporter (NCC) and cause hyperkalemia, tacrolimus was selected to treat NS. Following treatment with potassium chloride, magnesium oxide, low-dose glucocorticoid combined with tacrolimus, the fatigue significantly improved, and concurrently hypokalemia, hypomagnesemia were corrected and NS was remitted.. Renal biopsy should be warranted for GS patients with moderate to nephrotic-range proteinuria. Tacrolimus was preferred to the management of GS patients with NS.

Topics: Fatigue; Gitelman Syndrome; Glomerulonephritis, Membranous; Humans; Hypokalemia; Magnesium; Male; Potassium; Proteinuria; Solute Carrier Family 12, Member 3; Tacrolimus

Tacrolimus has been widely used in membranous nephropathy in recent years. The drug interactions of the coadministration of tacrolimus with omeprazole in CYP3A5 nonexpresser membranous nephropathy patients have not been demonstrated. Here, we report an idiopathic membranous nephropathy patient who was with CYP2C19*2/*2, CYP3A5*3/*3 (nonexpresser) and ABCB1 (3435 TT, 1236 computed tomography, 2677 TT) genotype requiring treatment with tacrolimus and omeprazole and found to have fluctuating metabolism of tacrolimus. This study shows that tacrolimus and omeprazole have pharmacologic drug interactions in CYP3A5 nonexpressers, implying that the CYP3A and ABCB1 gene mutations linked to tacrolimus metabolism may alter tacrolimus levels in the blood. The observed concentrations of tacrolimus were decreased after the discontinuation of omeprazole therapy. It demonstrates that, in addition to genotype, clinical covariates, such as omeprazole are important when it comes to better understanding and prediction of tacrolimus dosage. It is deemed necessary to monitor tacrolimus blood concentrations and make dose adjustments when patients were coadministered with omeprazole.

Topics: Cytochrome P-450 CYP3A; Genotype; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Omeprazole; Polymorphism, Single Nucleotide; Tacrolimus

Idiopathic membranous nephropathy (iMN) is recognized as an organ-specific autoimmune disease, mainly caused by anti-PLA2R antibody. This study aimed to study between anti-PLA2R antibody level at diagnosis and the response to tacrolimus (TAC)-based treatment in iMN patients.. This was a retrospective cohort study including 94 kidney biopsy-proven MN patients with positive anti-PLA2R antibody at diagnosis from May 2017 to September 2021 in our center. All iMN patients received the TAC regimen as the initial immunosuppressive therapy. All patients were divided into two groups according to anti-PLA2R antibody titer at diagnosis: high-level group (> 150 RU/ml; n = 42) and low-level group (≤ 150 RU/ml; n = 52). The association between anti-PLA2R antibody levels and clinical outcomes was assessed using the Kaplan-Meier method.. The low density lipoprotein in the high-level group was significantly higher than low-level group at diagnosis, otherwise, serum albumin was significantly lower than low-level group; however, there was no significant difference in creatinine levels between two groups. The remission rates were significantly higher in the low-level group than high-level group after treatment with TAC for 12, 18, or 24 months (all P < 0.05). After 12 months of treatment with TAC, 82.7% of the patients in the low-level group achieved complete remission (CR) or partial remission (PR) (mean, 6.52 ± 0.53 months). However, 38.1% of the patients in high-level group achieved CR or PR (mean, 9.86 ± 0.51 months). Moreover, CR rate at 12 months in the high-level group was only 4.7% (mean, 11.88 ± 0.63 months). The infection frequency in the high-level group (35.6%) was higher than the low-level group (20%) during the TAC treatment, although there was no significant difference (P = 0.065). There were 19% patients who had end-stage kidney disease (ESKD), and 7.1% of patients died of ESKD in the high-level group during the follow-up period.. Anti-PLA2R antibody level above 150 RU/ml at diagnosis can predict a poor treatment response and outcome of TAC treatment in iMN patients, who may not benefit from TAC or other calcineurin inhibitor regimens as the initial treatment.

Topics: Autoantibodies; Calcineurin Inhibitors; Glomerulonephritis, Membranous; Humans; Retrospective Studies; Tacrolimus

To assess the clinical profile and primary treatment response and outcomes in idiopathic membranous nephropathy (IMN) patients.. This study was carried out between December 2013 and January 2019 in a tertiary care hospital in North India on 2 years retrospective and 3 years prospective renal biopsy proven patients with IMN presenting with nephrotic syndrome. Basic baseline investigations carried out were urinary proteins, serum albumin, serum creatinine, other special tests wherever necessary or possible (including phospholipase A2 receptor antibodies), and different treatment regimens were offered for treatment. The patients were followed up for a minimum period of 6 months after administration of treatment.. The study was carried out in 120 patients with mean age of 43±14.6 years and male female ratio of 1.65:1. Hypertension was noted in 36%, microscopic hematuria in 13%, and mean 24 hours urinary proteinuria 10.5±3.1 gm. Complete or partial response at 6 months was observed in 57% and 34% cases to cyclophosphamide, 60% and 40% to modified Ponticelli treatment, 81% and 19% to tacrolimus, and 40% and 36% cases to rituximab. Relapse was observed in 6% of cyclophosphamide and 13% in tacrolimus groups.. Our results show a good and comparable response to cyclophosphamide, tacrolimus, and rituximab at 6 months of follow up. The cases which achieved complete remission had significantly lower baseline proteinuria compared to those who did not respond.

Topics: Adult; Cyclophosphamide; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Proteinuria; Retrospective Studies; Rituximab; Tacrolimus; Treatment Outcome

Given its narrow treatment window, high toxicity, adverse effects, and individual differences in its use, we collected and sorted data on tacrolimus use by real patients with kidney diseases. We then used machine learning technology to predict tacrolimus blood concentration in order to provide a basis for tacrolimus dose adjustment and ensure patient safety.. This study involved 913 hospitalized patients with nephrotic syndrome and membranous nephropathy treated with tacrolimus. We evaluated data related to patient demographics, laboratory tests, and combined medication. After data cleaning and feature engineering, six machine learning models were constructed, and the predictive performance of each model was evaluated via external verification.. The XGBoost model outperformed other investigated models, with a prediction accuracy of 73.33%, F-beta of 91.24%, and AUC of 0.5531.. Through this exploratory study, we could determine the ability of machine learning to predict TAC blood concentration. Although the results prove the predictive potential of machine learning to some extent, in-depth research is still needed to resolve the XGBoost model's bias towards positive class and thereby facilitate its use in real-world settings.

Topics: Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus; Technology; Treatment Outcome

Topics: Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Rituximab; Tacrolimus

Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.. A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.. The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.. At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.. Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.. Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.

Topics: Electroencephalography; Epilepsy; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Receptors, Phospholipase A2; Rituximab; Tacrolimus

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Rituximab; Tacrolimus

The STARMEN trial postulated that in primary membranous nephropathy (pMN) treatment with tacrolimus plus rituximab would be superior to a traditional Ponticelli regimen of alternating cyclophosphamide and glucocorticoids. This was not the case. Significantly more remissions were achieved in cyclophosphamide-treated patients, and more of these were complete remissions. Considering these results with those of the Mentor trial, which compared rituximab with cyclosporine in pMN, we offer an evidence-based perspective on the role of calcineurin inhibition for pMN treatment.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Rituximab; Tacrolimus

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Rituximab; Tacrolimus

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Glomerulonephritis, Membranous; Humans; Rituximab; Tacrolimus

BACKGROUND Tacrolimus may be effective in the short-term treatment of idiopathic membranous nephropathy (IMN). However, it is not clear whether an electron microscopic classification of the homogeneous and heterogeneous types of nephrotic IMN is related to the efficacy of tacrolimus in patients with IMN. This study aimed to explore this question and to provide evidence for individualized patient treatment. MATERIAL AND METHODS This 6-month retrospective study included 61 Chinese patients previously diagnosed with IMN. Patients received treatment was tacrolimus plus glucocorticoid. The patients were divided into a homogeneous group and a heterogeneous group based on the evaluation of electron-dense deposits. The initial clinicopathologic factors in the 2 groups were analyzed, and the difference in efficacy of tacrolimus in the 2 groups was assessed. The factors predicting remission were also studied. RESULTS No significant alteration in the initial clinicopathologic status was found between the 2 groups, except for proteinuria, serum albumin levels, systolic blood pressure, and renal biopsy results (stages I/II/III/IV). After 3 months of treatment, the difference in remission was not significant between the 2 groups. However, after 6 months of treatment, a significant difference in remission rates was observed between the 2 groups. The binary logistic model showed that the homogeneous nephrotic IMN was independently associated with total remission (partial plus complete remission), and was also related to complete remission. CONCLUSIONS The results of our study revealed that the homogeneous type of nephrotic IMN had a higher short-term remission rate and a predictive value for partial or complete remission, and it might be a meaningful marker of the short-term response to tacrolimus.

Topics: Adult; China; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Microscopy, Electron; Middle Aged; Nephrons; Precision Medicine; Prognosis; Retrospective Studies; Tacrolimus; Treatment Outcome

Kidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes.. Ninety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN).. At end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others.. Recipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.

Topics: Adult; Cyclosporine; Female; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

Guidelines recommend classical combined therapy of steroid and cyclophosphamide (CYC) for patients with idiopathic membranous nephropathy (IMN), while it is associated with severe adverse effects.. We conducted an observational and retrospective study to evaluate the effectiveness and safety of steroids plus tacrolimus (TAC) versus steroids plus CYC for IMN.. Over the 18-month observation period, the study suggested that the remission rates at the first 3 months were significantly higher in TAC group than in CYC group (72.1% vs 54.9%, P < 0.05). Although the cumulative incidence of serious and non-serious adverse events was not different significantly between the two groups, the incidence after first 3 months was lower in TAC group. Levels of 24-h UP and serum albumin improved in the TAC group more than in the CYC group (P < 0.05) over the observed period.. Because of its short-term effectiveness and long-term safety profile, steroid plus TAC might be a better option for IMN.

Topics: Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Neoplasm Recurrence, Local; Retrospective Studies; Tacrolimus; Treatment Outcome

Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although various studies have demonstrated the efficacy of tacrolimus combined with corticosteroids for treating IMN, both tacrolimus and corticosteroids have been shown to be diabetogenic, particularly following organ transplantation. Furthermore, the frequency and risk factors for new-onset diabetes mellitus (NODM) in IMN patients treated with tacrolimus plus low-dose corticosteroids remain unclear.. To evaluate the incidence of NODM in IMN patients undergoing tacrolimus plus low-dose corticosteroid therapy and to confirm the risk factors for NODM development.. This retrospective study recruited 72 eligible patients with biopsy-proven IMN from our center, between September 2013 and June 2018. All subjects were treated with tacrolimus plus low-dose corticosteroids for a minimum of 3 months. The primary outcome was NODM development during the follow-up period. The secondary outcome was complete or partial remission. Patients were divided into 2 groups: patients with NODM (NODM group) and those without NODM (No-NODM group). Demographic and clinical data at baseline and follow-up were assessed.. During follow-up, 31 of the 72 patients developed NODM (43.0%). The median time to occurrence was 3 months after treatment initiation. NODM patients were significantly older (median age 59 vs. 40 years) than No-NODM patients. Baseline fasting blood glucose levels were slightly higher in the NODM group; however, the difference was not significant (p = 0.07). Older age was an independent risk factor for NODM (OR 1.73 and 95% CI 1.20-2.47, p = 0.003). Overall kidney remission rates were 80.6%. There was no significant difference in remission rate between groups. There was a significant difference in development of pulmonary infection, which occurred in 7 NODM patients and only in 1 No-NODM patient (p = 0.018). IMN reoccurred in 5 NODM patients but only 1 No-NODM patient.. Tacrolimus plus low-dose corticosteroid therapy was an efficient treatment for IMN; however, it was accompanied by increased NODM morbidity, which should be considered serious, due to the increased risk of life-threatening complications. Increasing age was a major risk factor for NODM in IMN patients treated with tacrolimus plus low-dose corticosteroid therapy.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Diabetes Mellitus; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus

The current research aimed to investigate the correlation between the effect of Wuzhi soft capsule (WZC) on FK506 concentration and CYP3A5 gene polymorphism in patients with membranous nephropathy (MN).Seventy-five patients with idiopathic MN were enrolled and divided according to the expression of CYP3A5 gene metabolic enzyme into group A (CP3A5 metabolic enzyme function expression types CYP3A5*1/*1 type and CYP3A5*1/*3 type), and group B (non-expression type CYP3A5*3/*3 type). All patients were given oral administration of tacrolimus capsule at the initial dose of 1 mg for twice a day 1 hour before breakfast and dinner. Afterwards, the oral administration of WZC was added at the dose of 0.5 g for 3 times a day within half an hour after 3 meals.The blood concentrations of FK506 in groups A and B were significantly higher than those before administration. Compared with that before administration, the FK506 blood concentration was increased by 3.051 ± 0.774 ng/ml after adding the WZC. Besides, the blood concentrations of FK506 in group A were lower than those in group B before and after administration; meanwhile, the 24 hours total urine protein and the biochemical indexes in both groups displayed no statistically significant difference. Only 1 case of diarrhea was observed, which was relieved after the reduction of tacrolimus.Wuzhi soft capsule can significantly increase the blood concentration of FK506 in MN patients. Moreover, the CYP3A5 genotyping should be considered when WZC is used to increase the blood concentration of FK506.

Topics: Adult; Calcineurin Inhibitors; Capsules; Cytochrome P-450 CYP3A; Drug Synergism; Drugs, Chinese Herbal; Female; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Pharmacogenomic Testing; Polymorphism, Genetic; Precision Medicine; Tacrolimus

Membranous nephropathy (MN) caused by disease-modifying antirheumatic drugs is relatively common in patients with rheumatoid arthritis (RA). However, MN rarely occurs due to RA itself. We describe a 61-year-old woman with RA who showed nephrotic syndrome. She was admitted because of systemic edema and severe arthritis. She had a long history of RA successfully treated with methotrexate (MTX), but discontinued all treatments 4 years before hospitalization. She had never been treated with bucillamine or gold. Laboratory test results were positive for anti-cyclic citrullinated peptide antibody and negative for anti-nuclear antibody. Renal pathologic findings were compatible with MN. Immunofluorescence microscopy showed IgG, IgA, κ, λ, and C3 along the glomerular capillary wall, whereas deposition of IgM or C1q was not detected. In terms of the IgG subclasses, only IgG2 findings were positive. Results for glomerular antigen and serum antibody for M-type phospholipase A2 receptor and thrombospondin type 1 domain-containing 7A were negative. HLA type did not include the HLA-DQA1 gene that is a concern in primary MN (PMN). She responded to intensive immunosuppressive therapy consisting of prednisolone, tacrolimus, and MTX with a parallel reduction of proteinuria. Based on assessments for differentiating PMN from secondary MN (SMN), the diagnosis of the present case was incompatible with PMN. Taken together, we consider that SMN in the present case was due to RA itself rather than drug-induced MN.

Topics: Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Methotrexate; Middle Aged; Nephrotic Syndrome; Prednisolone; Proteinuria; Tacrolimus; Treatment Outcome

In China, the prevalence of idiopathic membranous nephropathy (IMN) is increasing with a younger age of onset. From January 2012 to October 2018, biopsy-proven nephrotic IMN patients aged between 15 and 40 in Taian City Central Hospital treated with tacrolimus (TAC) were retrospectively analyzed. Twelve-month follow-up data were collected. A total of 86 patients were enrolled in this study. Forty patients in the TAC group received TAC monotherapy with an initial dose of 0.05 to 0.1 mg/kg/day. Forty-six patients in the TAC + Pred group received TAC combined with oral prednisone (0.5 mg/kg/day initially). Remission rate, relapse rate, and adverse events in the two groups were assessed. Total remission (TR) rates at the end of the 3rd, 6th, and 12th month were 15%, 35%, and 77.5% (TAC group) and 28.3%, 56.5%, and 80.4% (TAC + Pred group), respectively. Compared with the TAC group, the TAC + Pred group had higher complete remission rates at the end of the 6th and 12th month, and TR rate at the 6th month was significantly higher. Twenty-four-hour urinary protein excretion, serum albumin and estimated glomerular filtration rate between the two groups were comparable during the follow-up. Decrease in proteinuria was significantly greater in the TAC + Pred group. No significant difference of relapse rate was found between the two groups. Adverse effects in the two groups were mild and controllable. Both TAC monotherapy and TAC combined with medium-dose prednisone are effective and safe for young adults with nephrotic IMN, while TAC + Pred regimen brings more benefits.

Topics: Adolescent; Adult; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Proteinuria; Retrospective Studies; Tacrolimus; Young Adult

Idiopathic membranous nephropathy (IMN) is one of the most common adult nephrotic syndromes. Some patients with this disorder require immunosuppressive therapy. This retrospective case series was performed to assess the effects of tacrolimus (TAC) combined with Tripterygium wilfordii polyglycoside (TWG) in treating IMN.. From January 2015 to August 2016, kidney-biopsy-proven IMN patients treated with TAC in the Chinese PLA General Hospital were screened. Data were retrieved from the patients' medical records. The first efficacy evaluation index was remission rate (complete remission and partial remission), and the secondary efficacy evaluation indices included relapse rate, proteinuria, serum albumin and estimated glomerular filtration rate (eGFR). Adverse events were also assessed.. The included patients' treatments were tacrolimus monotherapy (TAC group, n = 33), tacrolimus combined with methylprednisolone (MP) (TAC + MP group, n = 24) and tacrolimus combined with Tripterygium wilfordii polyglycoside (TAC + TWG group, n = 21). The remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 54.5, 62.5, and 85.7%, respectively (TAC + TWG group vs TAC group, P = 0.037, TAC + TWG group vs TAC + MP group, P = 0.125). Moreover, the complete remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 21.2, 20.8, and 57.1%, respectively (TAC + TWG group vs TAC group, P = 0.007, TAC + TWG group vs TAC + MP group, P = 0.012). Compared with the TAC group, the TAC + TWG group had a higher remission rate during these ten months (log-rank, P = 0.005). Compared with the TAC and TAC + MP groups, the TAC + TWG group had a higher complete remission rate (log-rank, P = 0.019 and log-rank, P = 0.005, respectively).. This retrospective study showed that TAC combined with TWG may be effective for treating IMN. Further randomized controlled trials (RCTs) are needed to assess the efficacy and safety of TAC combined with TWG.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Glycosides; Humans; Immunosuppressive Agents; Male; Middle Aged; Plant Extracts; Retrospective Studies; Tacrolimus; Treatment Outcome; Tripterygium

Tacrolimus is considered to be one of the main therapeutic options for idiopathic membranous nephropathy (IMN). This study aimed to investigate the association of variants in genes encoding the binding protein and the drug target (calcineurin) of tacrolimus with the efficacy in IMN patients and the potential mechanism. Sixty-seven IMN patients treated with tacrolimus were enrolled retrospectively. Sanger sequencing was performed to search for variants in all exons of the genes in 8 IMN patients and genotype for the detected variants in the other 59 patients. The molecular mechanism underlying the relationship between the variants and the efficacy was explored in human peripheral blood mononuclear cells (PBMCs) and other cell lines. Single nucleotide polymorphism rs875 (T > C) in the 3'untranslated region (3'UTR) of PPP3R1 encoding calcineurin regulatory subunit was found to be associated with the treatment efficacy of tacrolimus for IMN. Patients carrying TT genotype had a significantly higher remission rate than those carrying TC/CC genotype (83% vs. 47%, P = 0.008). Western blot showed that the TT genotype carriers exhibited reduced PPP3R1 protein levels in PBMCs (P = 0.02). Compared with C allele, T allele displayed increased binding affinity for miR-582-5p in the luciferase reporter assay (P < 0.001). Moreover, knockdown of PPP3R1 in Jurkat T cell line enhanced the immunosuppressive effect of tacrolimus. Our study revealed the association of PPP3R1 3'UTR polymorphism rs875 with the efficacy of tacrolimus in IMN patients. The functional polymorphism might alter PPP3R1 expression via modulating the interaction of miR-582-5p with PPP3R1, which further affected the immunosuppressive effect of tacrolimus.

Topics: 3' Untranslated Regions; Adult; Calcineurin; Disease Progression; Female; Gene Expression Regulation; Gene Frequency; Genotype; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Jurkat Cells; Male; MicroRNAs; Middle Aged; Polymorphism, Single Nucleotide; RNA, Small Interfering; T-Lymphocytes; Tacrolimus; Treatment Outcome

We evaluated the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in treating patients with idiopathic membranous nephropathy (IMN). One hundred seventy-seven biopsy-proven IMN patients were recruited in this retrospective clinical study. Sixty patients received TAC (target blood concentration of 4-8 ng/mL) and 117 patients received daily cyclophosphamide (CYC, 100 mg) combined with prednisone. Remission rates at the end of the first, second and third month in the TAC group were significantly higher than that in the CYC group (1st: 35.0 vs 19.7%, P<0.05; 2nd: 56.7 vs 38.5%, P<0.05; 3rd: 76.7 vs 59.0%, P<0.05). In the first 3 months, daily urinary protein and serum albumin in the TAC group obtained a better improvement than that in the CYC group (P<0.05). At the end of the sixth and the twelfth month, the remission rates, daily urinary protein and serum albumin were all comparable between the two groups (P>0.05). No significant difference of relapse rate between the groups was found (16.3 vs 12.0%, P>0.05). Patients were more likely to develop glucose intolerance in the TAC group. The TAC regimen obtained more benefits in treating IMN patients, especially in the first 3 months, than the CYC regimen.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Creatinine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Proteinuria; Reproducibility of Results; Retrospective Studies; Serum Albumin; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The KDIGO Clinical Practice Guidelines for Glomerulonephritis recommended tacrolimus as an alternative regimen for the initial therapy for Idiopathic membranous nephropathy (IMN), however, large observational studies evaluating tacrolimus treatment in IMN remains rare.. A total of 408 consecutive IMN patients with nephrotic syndrome who were treated with tacrolimus in Jinling Hospital were included. The effectiveness and safety of tacrolimus treatment in IMN were analyzed in this study.. The cumulative partial or complete remission after tacrolimus therapy were 50%, 63% and 67% at 6, 12 and 24 months, respectively, and the cumulative complete remission rates were 4%, 13% and 23%, respectively. Multivariate logistic analysis showed that higher tacrolimus exposure during induction treatment, female gender, higher eGFR and no history of previous immunosuppressive therapy were independently associated with higher probability of remission. A relapse occurred in 101 of the 271 (37.3%) patients with partial or complete remission, and 18 of the 95 (18.9%) patients with complete remission. Tapering duration of tacrolimus and complete remission versus partial remission status were independent factors associated with risk of relapse. A decline in eGFR was the most frequent adverse event during tacrolimus treatment. During tacrolimus treatment, a ≥40% decrease in eGFR was observed in 43 (10.5%) patients.. Low dose tacrolimus is effective for IMN, with a total remission rate of 66% whereas with a rather high rate of relapse. However, the safety of tacrolimus treatment needs to be further validated in large randomized clinical trials.

Topics: Adult; China; Cohort Studies; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Prevalence; Recurrence; Risk Factors; Sex Distribution; Tacrolimus; Treatment Outcome

An infant boy with steroid-resistant nephrotic syndrome (idiopathic membranous glomerulonephropathy) achieved remission with ciclosporin but developed eosinophilia and high IgE levels (max 19 000  iU/mL). Conversion to tacrolimus resulted in chronic diarrhoea (eosinophilic gastroenteritis), muscle weakness, polyserositis and failure-to-thrive. In contrast, a trial without tacrolimus resulted in a ciclosporin-responsive relapse, therapy-resistant focal seizures with generalised spikes, worsening muscle weakness and diarrhoea. The patient was weaned off of ciclosporin and completely normalised. In vitro testing demonstrated decreased viability of the patient's cells when incubated with calcineurin inhibitors (ciclosporin, 70%; tacrolimus, 80% compared to control cells), supporting their role in this adverse drug reaction.

Topics: Cell Survival; Cyclosporine; Deprescriptions; Drug Substitution; Enteritis; Eosinophilia; Failure to Thrive; Gastritis; Gingival Hyperplasia; Glomerulonephritis, Membranous; Humans; Hypertrichosis; Immunosuppressive Agents; In Vitro Techniques; Infant; Kidney Glomerulus; Male; Microscopy, Electron; Muscle Weakness; Seizures; Serositis; Tacrolimus; Vasculitis

A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

Topics: Female; Glomerulonephritis, Membranous; Graft Rejection; Hepatitis C; Histocompatibility Antigens Class I; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Methylprednisolone; Middle Aged; Prednisolone; Reoperation; Tacrolimus; Time Factors; Treatment Outcome

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Phospholipases A2; Prednisolone; Proteinuria; Receptors, Phospholipase A2; Recurrence; Respiratory Tract Infections; Tacrolimus; Treatment Outcome; Young Adult

Although tacrolimus is recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of idiopathic membranous nephropathy (MN), little is known about factors that influence response and relapse of the disease after tacrolimus therapy.. Multicentre study that collected 122 MN patients with nephrotic syndrome and stable renal function treated with tacrolimus. Duration of treatment was 17.6 ± 7.2 months, including a full-dose and a tapering period.. The percentage of remission was 60, 78 and 84% after 6, 12 and 18 months of treatment, respectively. The amount of proteinuria at baseline significantly predicted remission, the lower the baseline proteinuria the higher the probability of remission. Only 10 patients (8%) received concomitantly corticosteroids, and their rate of remission was similar (80% at 18 months). Among responders, 42% achieved complete remission (CR) and 58% partial remission (PR). Almost half (44%) of the responder patients relapsed. The amount of proteinuria at the onset of tacrolimus tapering was significantly higher in relapsing patients. By multivariable analysis, the presence of a PR versus CR at the onset of tacrolimus tapering and a shorter duration of the tapering period significantly predicted relapses. Tolerance was good and the number of adverse events low.. Tacrolimus monotherapy is an effective and safe option for the treatment of MN with stable renal function. Relapses are frequent in patients with PR and can be partially prevented by a longer tapering period.

Topics: Case-Control Studies; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Incidence; Longitudinal Studies; Male; Middle Aged; Prognosis; Proteinuria; Recurrence; Remission Induction; Retrospective Studies; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Calcineurin Inhibitors; Cyclophosphamide; Drug Resistance; Glomerulonephritis, Membranous; Humans; Middle Aged; Prospective Studies; Tacrolimus

To investigate the clinical characteristics and histopathological features of kidney disease in elderly patients.. We retrospectively analyzed the results of 4,185 consecutive renal biopsies, and 288 patients aged >60 years at the Second Hospital of Jilin University from January 1998 to December 2013 were finally included. All patients had been clinically and histologically diagnosed with kidney disease.. Nephrotic syndrome was the main clinical indication for biopsy. Twenty-four patients (8.33 %) experienced a minor complication related to their biopsy procedure. Among patients diagnosed as primary glomerulonephritis (GN), membranous nephropathy (MN) was the most frequent subclassification (24.7 %), followed by mesangioproliferative glomerulonephritis (MsPGN, 11.1 %) and IgA nephropathy (IgAN, 8.0 %). Amyloidosis (8.7 %) was the most common secondary GN, followed by antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune GN (5.2 %) and diabetic nephropathy (DN, 3.8 %). Based on renal biopsies results, 143/288 patients received immunosuppressive therapy and showed an overall remission rate (complete plus partial remissions) of 74.1 %. Among 71 MN patients, 29 patients received steroids plus cyclophosphamide and showed a remission rate of 79.3 %, while 42 patients received steroids and tacrolimus and showed a remission rate of 90.5 %. Among 25 patients with amyloidosis, 22 cases received melphalan plus dexamethasone and showed a remission rate of 40.9 %, while three patients received vincristine, adriamycin, and dexamethasone and showed a remission rate of 66.7 %.. Making an accurate pathologic diagnosis by renal biopsy is crucial for selecting the proper treatment for elderly patients with kidney disease.

Topics: Aged; Aged, 80 and over; Amyloidosis; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Antineoplastic Agents, Alkylating; Autoimmune Diseases; Biopsy; Cyclophosphamide; Dexamethasone; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Retrospective Studies; Tacrolimus; Treatment Outcome

The level of circulating antibodies against M-type phospolipase A2 receptor has been reported as having a significant correlation with clinical activity in idiopathic membranous nephropathy. However, the usefulness of monitoring antibody titre as a predictor of clinical response following the onset of treatment has not been formally analysed. The predictive value of the evolution of anti-PLA2R antibody titre on the clinical response of idiopathic membranous nephropathy patients treated with tacrolimus is analysed in the following study.. 36 patients with nephrotic syndrome secondary to idiopathic membranous nephropathy with immunosuppressive treatment indication criteria were treated with tacrolimus in monotherapy. The level of anti-PLA2R antibodies was determined before treatment and at 3, 6, 9 and 12 months after the onset of treatment. The study analysed the predictive value of the reduction in antibody titre and the relative and absolute reduction in antibody titre at 3 and 6 months over the period until remission and on the probability of remission at 6, 9 and 12 months.. The relative reduction in the anti-PLA2R antibody titre was significantly greater in those patients with remission and it preceded the clinical response. No association was observed between the antibody titre prior to treatment and the mean response time or the response at 12 months. Reduction in antibody titre is significantly associated with the time until signs of remission. Relative reduction in anti-PLA2R antibody titre at 3 months had a high sensitivity and specificity to predict the response at 6 and 9 months, but not at 12 months; however the relative reduction in the antibody titre at 6 months had a high sensitivity and specificity for predicting the response at 12 months.. In patients with IMN associated with anti-PLA2R antibodies, the monitoring of antibody titre following the onset of treatment is useful for estimating the time period until remission and predicting the probability of remission at 12 months.

Topics: Adult; Antibodies; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Predictive Value of Tests; Receptors, Phospholipase A2; Tacrolimus; Treatment Outcome

Tacrolimus is an anticalcineurinic agent with potent immunosuppressive activity that has recently been shown to have the added benefit of reducing proteinuria in membranous nephropathy (MN) patients. However, its potential mechanisms remain unknown. To reveal the mechanism, rat cohorts were administered tacrolimus or vehicle from days 7 to 28 after the induction of passive Heymann nephritis (PHN). PHN induction resulted in heavy proteinuria and increased expression of desmin, a marker of injured podocytes. We also showed that the glomerular expression of angiopoietin-like-4 (Angptl4) was markedly upregulated in PHN rats and human MN followed by an increase in urine Angptl4 excretion. In addition, increased Angptl4 expression may be related to podocyte injury and proteinuria. Furthermore, upregulated Angptl4 expression primarily colocalized with podocytes rather than endothelial or mesangial cells, indicating that podocytes may be the source of Angptl4, which then gradually migrated to the glomerular basement membrane over time. However, tacrolimus treatment markedly reduced glomerular and urinary Angptl4, accompanied by a reduction in the established proteinuria and the promotion of podocyte repair. Additionally, glomerular immune deposits and circulating IgG levels induced by PHN clearly decreased following tacrolimus treatment. In conclusion, this is the first demonstration that the calcineurin inhibitor tacrolimus can reduce Angptl4 in podocytes accompanied by a decrease in established proteinuria and promotion of podocyte repair in MN.

Topics: Adult; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Calcineurin Inhibitors; Disease Models, Animal; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Male; Middle Aged; Podocytes; Proteinuria; Rats; Tacrolimus; Up-Regulation; Young Adult

Standard treatment for class III, IV, and V lupus nephritis (LN) is a combination of oral corticosteroids and mycophenolate mofetil (MMF). There is an estimated failure rate of 16%. Several small studies have looked at the use of tacrolimus in class III, IV, and V LN, both as induction treatment and as maintenance in patients refractory to other treatments. The majority of these studies were conducted in Asian patients. We discuss a cohort of eight female patients of various ethnicities with biopsy proven LN. All patients were evaluated retrospectively. Six were started on tacrolimus after failing to respond to MMF and corticosteroids, and one was started on tacrolimus alone because treatment options were limited by pregnancy. Five were Caucasian, one African American, one Hispanic, and one Vietnamese. Mean tacrolimus dose was 3.3mg daily (range 2-5 mg) titrated to a mean level of 3-6 ng/dl (range 3-6.6 ng/dl) for a mean of duration of 16 months (range 2-54 months). Six patients experienced complete remission (proteinuria <0.33 g/day), and two patients had a partial remission (minimum of 50% reduction in baseline proteinuria). Albumin increased an average of 32%. Average C3/C4 levels were 64/15 mg/dL, respectively, prior to treatment, and 95/25 mg/dL following treatment. No treatment-limiting adverse effects were reported. Our case series supports the growing body of evidence that tacrolimus is an effective therapy in LN patients with refractory proteinuria. Further studies are required to establish the long-term safety and efficacy of tacrolimus.

Topics: Adult; Female; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Proteinuria; Retrospective Studies; Tacrolimus; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Dacarbazine; Doxorubicin; Glomerulonephritis, Membranous; Hodgkin Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Remission Induction; Tacrolimus; Time Factors; Vinblastine

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Biomarkers, Tumor; Carcinoma, Renal Cell; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Kidney Transplantation; Male; Mucin-1; Mycophenolic Acid; Nephrectomy; Postoperative Complications; Reoperation; Tacrolimus

Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.

Topics: Administration, Oral; Animals; Cell Line; Complement Membrane Attack Complex; Cytoprotection; Desmin; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Glomerulonephritis, Membranous; Heymann Nephritis Antigenic Complex; Immunoglobulin G; Immunosuppressive Agents; Mice; NADPH Oxidases; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Podocytes; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Signal Transduction; Tacrolimus; Time Factors

Topics: Clinical Protocols; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cyclosporine; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Rituximab; Tacrolimus

The treatment of idiopathic membranous nephropathy is heavily debated because of wide variation in outcome. A rational treatment strategy is needed to appropriately administer conservative treatment to the low-risk group but immunosuppressive therapy to those with medium or high risk of renal deterioration. Currently, combinations of steroids with alkylating agents are best studied. Newer forms of immunosuppressive treatment are currently under study.

Topics: Adrenal Cortex Hormones; Angiotensin-Converting Enzyme Inhibitors; Cyclosporine; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Function Tests; Nephrotic Syndrome; Tacrolimus

A 22-year-old woman hospitalized for polyarthralgia was diagnosed with systemic lupus erythematosus (SLE). She was treated with prednisolone, and her clinical manifestations improved. However, she was re-admitted for renal biopsy because of persistent hypocomplementemia and development of proteinuria. The biopsy revealed segmental spike formation of basement membrane and subepithelial immune complex deposition, and membranous lupus nephritis (class V) was diagnosed. When tacrolimus was added to prednisolone, the serum complement titer quickly improved and proteinuria disappeared after about 11 months. Nevertheless, when tacrolimus was replaced examination showed cyclosporine due to gastrointestinal symptoms, she complained about arthralgia. Examination showed drop in the serum complement titer and recurrence of proteinuria. Renal biopsy at the time of recurrence showed increased subepithelial immune complex deposition in the capillary loops as compared to the first biopsy, a high degree of thickening of the basement membrane, and segmental circumferential interposition in some of the glomeruli. Membranous lupus nephritis (classes V + III) was diagnosed. By changing to tacrolimus and higher doses of steroids, the serum complement titer improved and proteinuria disappeared. This case indicates that tacrolimus can be an effective therapeutic agent for membranous lupus nephritis.

Topics: Adult; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Tacrolimus; Treatment Outcome

To evaluate the efficacy of FK506 in the treatment of children with nephrotic syndrome of different underlying pathology.. 12 patients were treated with FK506 with a dosage of 0.1 - 0.15 mg/kg/d while corticosteroid dose was tapered stepwise. This therapeutic course lasted 3 - 6 months during which the plasma concentration ofFK506 was monitored.. 12 children with different pathological types nephrotic syndrome were treated with FK506, including 4 cases of MCN, 6 cases of MsPGN, and 1 case of MPGN and 1 case of FSGS. After 2-month duration, 8 patients got complete remission including 4 cases of MCN and 4 cases of MsPGN and 3 children including 1 case of MsPGN, 1 case of MPGN, and 1 case of FSGS got partial remission. Only 1 child with MsPGN was considered to be a treatment failure. The overall response rate was 91.67% with the plasma concentration of FK506 maintained at 5 approximately 12 ng/ml, and the response time was 10 - 38 days. After 1-month duration, all patients except one experienced a reduction in proteinuria to normal levels or a partial response (50% reduction in protein excretion), significant increase in serum albumin, decrease in serum cholesterol and triglyceride and disappearance of edema. 2 months later, in 11 patients, blood biochemical values had returned to normal levels. The drug was generally well-tolerated. 3 patients had anorexia, nausea, vomiting. 2 patients experienced transient elevated serum creatinine which was reversible after the adjustment of dosage. 3 patients had minor changes in urine NAG. Only 2 of all patients relapsed.. FK506 is one of the effective immunosuppressants. In this study, FK506 in combination with a small doses of steroid while decreasing FK506 dosage plays a role in consolidating the curative effect and preventing relapse. In conclusion, FK506 may be effective in the treatment of nephrotic syndrome.

Topics: Adolescent; Adrenal Cortex Hormones; Child; Child, Preschool; Female; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Tacrolimus

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

To study the efficacy and safety of tacrolimus in primary membranous nephropathy.. We describe 3 patients with primary membranous nephropathy who were either resistant to or could not tolerate steroid with or without cytotoxic agents. They were treated with tacrolimus 0.2 mg/kg/day for 6 months. The dosage of tacrolimus was adjusted to keep a whole blood tacrolimus level of 5-10 ng/ml.. One patient had almost complete disappearance of proteinuria while the other 2 had at least 50% reduction in proteinuria. Proteinuria increased again in 2 of the patients after tacrolimus was stopped, but in neither of them proteinuria returned to the pretreatment level 6 months after tacrolimus was stopped.. We conclude that tacrolimus may have a modest efficacy in the treatment of resistant membranous nephropathy.

Topics: Adult; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Proteinuria; Tacrolimus

Topics: Adult; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Recurrence; Renal Veins; Tacrolimus; Thrombosis

There have been no reports on the effect of FK5 06, a new immunosuppressive agent, on experimental membranous glomerulonephritis (MN) induced by an exogenous antigen. Therefore we investigated the effects of FK506 on MN induced by cationized bovine serum albumin (C-BSA) in rats.. Two weeks after the rats were immunized with 1 mg of C-BSA and Freund's complete adjuvant, they received intravenous injections of 3 mg/kg of C-BSA 3 times weekly for 4 weeks. Rats were divided into four groups: group A (n = 5) received intramuscular injections of 3 mg/kg of FK506 daily for 5 days beginning 2 days before the first immunization; group B (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 2 weeks after the first immunization; and group C (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 4 weeks after the first immunization. Group D (n = 5) received no FK506 and served as the control group. Rats were sacrificed 8 weeks after the first immunization.. Administration of FK506 in the preimmunization stage almost completely suppressed the development of MN in group A. Histological findings in groups B and C were similar to those in group D, the control group. However, urinary protein excretion was significantly lower in group B (24+/-46 mg/day) and C (220+/-44 mg/day) than in group D (330+/-61 mg/day). Expression of intracellular adhesion molecule-1 in glomeruli and the number of leukocyte functioning-associated molecules-1 were significantly decreased in groups A, B, and C compared with the control group. Administration of FK506 was not associated with any significant side-effects or histological abnormalities. The whole-blood trough levels of FK506 in groups B and C were 9.1 ng/ml and 9.2 ng/ml respectively.. The efficacy of FK506 was significantly increased when the drug was administered in the early phase of immunization in this model. The present study suggests that FK506 may be useful in patients with intractable nephrotic syndrome such as MN.

Topics: Animals; Creatinine; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Glomerulonephritis, Membranous; Immunosuppressive Agents; Injections, Intramuscular; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Lymphocyte Function-Associated Antigen-1; Proteinuria; Rats; Rats, Wistar; Serum Albumin; Serum Albumin, Bovine; Tacrolimus

We describe a case of de novo membranous glomerulopathy in the renal allograft of a diabetic patient, treated with the newer immunosuppressive agent FK 506. Twenty-two months later this patient developed nephrotic range proteinuria.

Topics: Basement Membrane; Cyclosporine; Diabetic Nephropathies; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Microscopy, Fluorescence; Middle Aged; Tacrolimus; Treatment Outcome