The authors have declared that no competing interests exist.
Conceived and designed the experiments: GX JX CY ZM CM. Analyzed the data: GX JX CY ZM CM DC XH LL LS XZ. Contributed reagents/materials/analysis tools: CX YM LY. Wrote the paper: GX JX ZM CY LY.
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
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.
Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome for adults in western counties, as well as in China. Although 30% patients showed spontaneous complete or partial remission of nephrotic syndrome
A meta-analysis
Immunosuppressive treatment has been widely used in the treatment of IMN worldwide. However, there are still big controversies over the efficacy and safety of different immunosuppressive agents treatments in IMN, especially for those relatively new agents like, tacrolimus (TAC) and leflunomide (LET). So a meta-analysis comparing the efficacy and safety of different immunosuppressive agents in the treatment of Chinese adults with nephrotic IMN makes sense. China is the country with largest population of the world. To exclude the interferences caused by the ethnic variety, this meta-analysis was made on Chinese adults base.
We tried to include all the RCTs that assess the efficacy and tolerability associated with the comparison of different immunosuppressive agents for the treatment of Chinese adults with nephrotic IMN. PubMed (up to December 2011), EMBASE (1980 to December 2011), and Cochrane Library (Issue12, 2011) and the databases in Chinese including
Prospective RCTs compared different immunosuppressive agents.
The selected patients were Chinese adults suffering from IMN, aged 16 years or older, with nephrotic syndrome.
The diagnosis of IMN was made by renal needle biopsy.
Study design without randomization, own control or compared with different usage of the same agent.
Secondary types of membranous nephropathy or not Chinese patients.
Trials including the use of traditional Chinese medicine were excluded,for its unknown additional effects on immunosuppressive agents and uncertain dose of active components. We also excluded studies where it was impossible to identify how many patients had nephrotic syndrome, after checking the baseline evaluations and contacting with the authors.
Two reviewers(G. Xie and J. Xu) independently assessed the eligibility of each article to be included in this meta-analysis, and this work was checked by another author (Z. Mao).
Data were extracted from each identified trial by two researchers (G. Xie and J. Xu) with a predesigned review form (Microsoft Office Excel 2007) independently, and any disagreement was resolved by discussion. Authors of the original studies were consulted through emails for suggestions if any problem occurred.
The following data were included: the authors of each study, the year of publication, the design of the trial, the duration of the study, the sample size, the age and gender of the patients, the interventions (mainly immunosuppressive agents, dose and usage), the baseline proteinuria/serum creatinine/serum albumin values, the final proteinuria/serum creatinine/serum albumin values, and the therapeutic remission of participants (complete remission, partial remission). In addition, we retrieval the side effects including elevated liver enzymes, renal toxicity, infections, digestive symptoms, leukocytopenia, and other recorded.
The quality of included studies were evaluated by two authors (C Ye and D Chen) independently based on the standard criteria (randomization, blinding, and loss to follow-up)using the scoring system developed by Jadad
Statistical analyses were performed with Review Managerver 5.0.20 (Cochrane Collaboration, Oxford, UK). We assessed the heterogeneity of the trial results by calculating a chi-square test of heterogeneity and the I2measure of inconsistency. Dichotomous data were summarized as risk ratio (RR) and 95% confidence intervals (CIs), continuous ones (final proteinuria) as weighted mean difference (WMD) and 95% CIs as well.
The Flowchart of this meta-analysis was shown in
All included trials were prospective RCTs, 3
Trials | Number | Length | Mean age(year) | Gender male/female | Baseline proreinuria(g/day) | Initial steroids dose | Quality grade |
CyA versus CTX | |||||||
Li GF 2011 |
76 | 12 months | 45.2/44.8 | 49/27 | 5.4±2.3/5.0±2.1 | PDN0.5 mg/kg/d | 2 |
Wu QX 2011 |
40 | 12 months | 36.2 | 29/11 | 6.2±3.5/5.9±4.1 | aPDN0.8 mg/kg/d | 2 |
LET versus CTX | |||||||
Li GF 2011 |
80 | 6 months | 48.3/47.6 | 63/17 | 3.59±1.18/3.72±1.23 | PDN0.5 mg/kg/d | 2 |
Zhou W 2009 |
30 | 12 months | 42.8/41.6 | 15/15 | 7.84±3.73/7.78±3.67 | Prednisolone 0.8–1.0 mg/kg/d | 3 |
Zhu KY 2009 |
40 | >6 months | 51 | 24/16 | 6.15±2.36/6.17±2.53 | aPDN30 mg/d | 2 |
Zhang W 2011 |
60 | 12 months | 43.6/43.6 | 38/22 | 7.55±3.66/7.48±3.63 | PDN0.5/1.0 mg/kg/d | 3 |
Zhou W 2009 |
40 | 12 months | 43.8/42.6 | 17/23 | 7.93±3.82/7.62±3.55 | Prednisolone 0.8–1.0 mg/kg/d | 3 |
Li MX 2004 |
40 | 12 months | 45.5 | 29/11 | 5.01±1.78/5.15±1.87 | PDN1.0 mg/kg/d | 2 |
An WW 2009 |
32 | 12 months | 53.6 | 20/12 | 8.4±2.2/NC | Prednisolone60 mg/d | 2 |
Ren Y 2011 |
52 | 12 months | 46.6/41.1 | 36/16 | NC | PDN0.8–1.0 mg/kg/d | 1 |
TAC versus CTX | |||||||
Bai GZ 2011 |
32 | 9 months | 48.2 | 21/11 | NC | PDN15–60 mg/d | 1 |
Xu J 2010 |
24 | 24 months | 55.0/54.6 | 15/9 | NC | NC | >3 |
Chen M 2010 |
73 | 12 months | 47.2/48.6 | 41/32 | 7.11±3.93/7.28±3.91 | PDN1 mg/kg/d | 3 |
Chen WZ 2009 |
17 | 9 months | NC | NC | 4.0±0.7/3.9±1.6 | PDN15–60 mg/d | 2 |
Liu JP 2009 |
20 | 6 months | 51.3 | 13/7 | NC | PDN1 mg/kg/d | 2 |
MMF versus chlorambucil | |||||||
Chan TM 2007 |
20 | 15 months | 49.5 | 13/7 | 4.9(3.4–6.9)/5.8(4.1–8.1)median (range)/median(range) | Prednisolone 0.8/mPDN1g×3 days thenPrednisolone 0.4 mg/kg/d | 3 |
TAC versus LET | |||||||
Sun GD 2008 |
20 | 6 months | 49.5 | 14/6 | 9.87±2.45/8.96±1.79 | PDN30 mg/d | 2 |
Abbreviations: PDN, prednisone; aPDN, prednisone acetate; NC, not clear.
Seven trials
5 studies
5 studies
3 studies
Only 2 studies
Only 1 study
As side effects in a single comparison was not easy to make a statistical analysis, the major side effects of each agents were showed as following. 325 patients were given cyclophosphamide in total, and adverse events in 309 patients were reported: 42(13.6%) with dysfunction of liver, 37(12.0%) with leukocytopenia, 28(9.1%) with digestive symptoms. Hypertrichosis was the most frequent side effect of CyA (9/60, 15%). Elevated blood glucose happened in 18/78(23.1%) patients treated with TAC, 3 of which developed diabetes mellitus. 8/78(10.3%) patients treated with TAC got elevated blood pressure, and were treated with increased anti-hypertension drugs.
Eight among 112 (7.1%) patients given MMF got digestive symptoms. 6/75(8.0%) patients given LET got elevated liver enzymes, anther 8% got digestive symptoms.
There was no obvious nephrotoxicity directly related to immunosuppressive agents. 3 patients reported transient elevation of Scr in the comparison of “TAC versus CTX”, 2 for CTX, 1 for TAC, and none of them progressed to renal failure. Sun GD et al
The funnel plots (
We conducted a sensitivity analysis focus on the quality and patients of trials to assess the robustness of this meta-analytical results.
An analysis was performed by excluding low quality trials. As shown in
Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. Immunosuppressive agents acts predominate in its treatment for its benign or indolent course. As single-use glucocorticoids showed no benefit on IMN
The object of this meta-analysis was to compare the efficacy and safety of different immunosuppressive in the treatment of Chinese adults with nephrotic IMN, providing some updated references to nephrologists for making optimal therapy. By limiting trials conducted in Chinese adults, we aimed to exclude the interference of ethnic differences on the response to immunosuppressive treatment, as some studies
None of the studies involved reported the long-term outcome, like mortality or ESRD requiring initiation of dialysis or kidney transplantation. This analysis only viewed the short-term parameters to evaluate efficacy, including the final proteinuria/serum creatinine/serum albumin values and the therapeutic remission of participants (complete remission, partial remission). Serum creatinine is a value determined by multifactor, and has not showed obvious change during short-term follow up. Final proteinuria and serum albumin has correlation with the therapeutic remission, so the authors mainly analysed the latter. The most frequent definition usually adopted for “partial remission” was proteinuria between 0.3–2.0 g/24 h or decreased to lower by half. For “complete remission” the usual definition was proteinuria of less than 0.3 g/24 h and serum albumin more than 35 g/L and a normal renal function. However these definitions can be heterogeneous.
Cyclophosphamide as a classical immunosuppressive agent used in Chinese nephrotic IMN patients, was compared with other relatively new immunosuppressive agents, including LET, MMF, TAC and CyA. There were heterogeneous in the usage of cyclophosphamide: in 3 trials
Sensitivity analysis was performed by excluding low quality trials, did not substantially change the main results. This meta’s result “calcineurin inhibitors inducing more remission than alkylating agents” coincided with the earlier meta
Short-term duration (6–24 mouths), only one trial
In conclusion, based on Chinese adults and short duration RCTs, calcineurin inhibitors, especially TAC, showed superior potency to induce remission in nephrotic IMN with tolerable adverse effects, compared to alkylating agent (CTX).