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      Efficacy and safety of tacrolimus vs cyclophosphamide in the therapy of patients with idiopathic membranous nephropathy: a meta-analysis

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          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, P=0.15; 12-month: OR=2.17, 95% CI: 0.56–8.44, P=0.27). But TAC had better 6-month total remission (TR; total CR plus partial remission [PR]) than CTX (6-month: OR=2.62, 95% CI: 1.38–4.96, P=0.003; 12-month: OR=1.74, 95% CI: 0.29–10.48, P=0.54), and got a lower proteinuria after 6-month treatment (OR=−0.80, 95% CI: −1.53 to −0.07, P=0.03). TAC had a lower incidence rate on leucopenia than CTX, but had a tendency towards higher blood creatinine. In the meantime, tremor in TAC group was higher than that in CTX group. The differences on other adverse effects such as gastrointestinal syndrome, infection, herpes zoster, hypertension, liver function disorder and hyperglycemia were also analyzed. However, none of them were statistically significant.


          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.

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          Most cited references 13

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          Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

          A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.
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            Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.

             M Praga,  V Barrio,   (2007)
            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.
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              Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: a multicenter randomized controlled trial.

               Ming-Lu Liang,  ,  Wang Li (2010)
              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.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                03 July 2019
                : 13
                : 2179-2186
                [1 ]Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College , Shantou, People’s Republic of China
                [2 ]Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University , Guangzhou, People’s Republic of China
                Author notes
                Correspondence: Tianbiao ZhouDepartment of Nephrology, The Second Affiliated Hospital, Shantou University Medical College , No. 69 Dongsha Road, Shantou515041, People’s Republic of ChinaTel +86 136 7040 2516Email zhoutb@ 123456aliyun.com

                These authors contributed equally to this work

                © 2019 Lin et al.

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                Page count
                Figures: 3, Tables: 2, References: 17, Pages: 8
                Original Research


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