Background
Immunoglobulin A nephropathy is the most common type of glomerulonephritis in the world [
1,
2] and causes end-stage renal disease (ESRD) in a significant percentage of patients [
3‐
5]. About 1–2% of patients who are newly diagnosed with IgA nephropathy will develop ESRD each year [
6]. Some clinical markers such as impaired kidney function, sustained hypertension, and heavy proteinuria (over 1 g per day) are associated with poor prognosis [
7‐
9]. Most of the current treatment strategies including blood pressure (BP) control, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), lead to a reduction of proteinuria and are also commonly used in patients suffering from other chronic kidney diseases. However, there is still no specific treatment to date available for IgA nephropathy because its pathogenic mechanisms remain incompletely understood.
Mycophenolate mofetil (MMF), which is used as an immunosuppressant in patients undergoing renal transplants, might be an option for immunosuppressive treatment of patients with autoimmune diseases [
10,
11]. However, the efficacy of MMF therapy in IgA nephropathy is controversial. Several reviews evaluated the use of MMF in IgA nephropathy patients but they were published too early to include novel trials or lacked sufficient safety evaluations [
12‐
14].
In this systematic review, we sought all available randomized controlled trials (RCTs) to comprehensively evaluate the efficacy and safety of MMF therapy in IgA nephropathy.
Methods
Data sources and search strategy
We searched electronic databases of MEDLINE, EMBASE, the Cochrane Library, Chinese Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI) up to August 2014 with relevant key words and medical subject headings covering IgA nephropathy, IgA, GN, IgAGN, Berger’s disease, mycophenolate mofetil, mycophenolic acid, MMF, CellCept, controlled clinical trial, RCT, randomized controlled trial, and drug therapy without any language restriction (Additional file
1). Studies were excluded if they were not RCTs or had a follow-up period of less than 6 months. Manual scanning of reference lists from identified trials and review articles was done to identify any further studies that may have been relevant. All our work in this systematic review referred to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Additional file
2) [
15]. All analyses were based on previous published studies, thus no ethical approval and patient consent are required.
Study selection criteria
We included studies with biopsy-proven IgA nephropathy patients, aged ≥18 years old, with daily proteinuria ≥ 1 g but no malignancy and those studies comparing the efficacy of MMF with control or other immunosuppressive agents.
Studies that were not RCTs, or those with follow-up periods of less than 6 months were excluded.
Data extraction and quality assessment
Information from each trial was separately extracted by two authors (Chen YY and Li YM) using standard data-extraction forms. The extracted data included the baseline information of participants, proteinuria level, doses and duration of MMF use, follow-up duration, clinical outcomes, and adverse events.
Regarding any study with several publications, all the reports were grouped together. For some, information that was not reported in the publication or was presented in diagrams only, the investigators contacted the authors to seek the missing data.
Two additional authors (Yang SL and Li Y) who were not blind to authorship or journal of publication were responsible for the study quality, which included allocation concealment, blinding and completeness of follow-up [
16].
Outcome measures
The primary outcome was therapeutic effect. This included complete remission, defined as a value for urinary protein excretion that was below 0.3 g/24 h and a normal serum creatinine (Scr) level; significant remission, defined as a decline in urinary protein excretion by 50% or more over baseline value and a decline of Scr by 20% or more; partial remission, defined as decline in urinary protein excretion between 30 and 50%, as well as a relatively stable Scr level (variation less than 20%); treatment failure, defined as those failing to meet the standards outlined above.
The rate of therapeutic effect was calculated using the equation: effective rate = complete remission rate + significant remission rate + partial remission rate.
Secondary outcomes were ESRD, 50% increase in Scr, reduction of proteinuria and adverse effects.
Statistical analysis
Analyses were performed using Review Manager 5.1. The results of dichotomous outcomes (therapeutic effects, ESRD events, doubling Scr increases and adverse reaction) were expressed as risk ratios (RR) with 95% confidence intervals (CI). The mean difference (MD) was obtained when continuous scales of measurement were used to assess the treatment effects (e.g. proteinuria) and the standardized mean difference (SMD) was obtained when different scales were used. Inter-study heterogeneity was assessed by using the chi-square test and subgroup analysis was performed when high heterogeneity between studies existed. A random-effects model was used in this study because such models are generally considered to be more conservative [
17].
Discussion
In this systematic review, eight RCTs were included, covering 357 patients in total. No difference was found between MMF and other treatments or controls in the therapeutic effect or the effect on proteinuria, while subgroup analysis indicated that duration of MMF use of less than 18 months may have better therapeutic effects such as a 30–50% decrease in urinary protein as well as a relatively stable or 20% decrease in Scr. The satisfactory tolerance for MMF over a relatively short time course or some unpredictable side effects after longer term use of MMF may explain why a shorter duration of MMF treatment was beneficial. However, only one study, including 34 patients, assessed the effects of longer term therapy with MMF, but its follow-up period was too short. Therefore, based on this observation, the benefits of a short term treatment with MMF are yet to be irrefutably confirmed. No statistically significant difference was found in the MMF group compared with other therapies, either in the need for renal-replacement therapy or in the outcome of 50% increase of Scr. As for the comparison between MMF and other immunosuppressants, MMF may be considered superior to CTX with better clinical therapeutic effect.
When comparing the MMF-treated and control groups, no difference was found either in the effect of ESRD or in the effect of a 50% increase in Scr. However, Sydney Tang et al. [
28] extended their original study [
23] by following 40 Chinese patients with established IgA nephropathy for 6 years to evaluate the long term effect of MMF treatment. They found two (10%) patients in the MMF group and nine (45%) patients in the control group developed progressive renal failure that required dialysis at the end of this 6-year follow-up. This hints that MMF may have a long term effect of renoprotection. In a self-controlled clinical trial, Dario Roccatello et al. [
29] found that parameters including Scr, proteinuria and microscopic hematuria significantly dropped at 6 months and remained lower at the end of a follow-up period of 51 months. In this systematic review, the follow-up period of the included trials was too short (range 6 to 36 months) to detect long term effects of MMF therapy. In some observational studies, MMF combined with low-dose prednisone with duration of around 12–18 months can reduce proteinuria and preserve renal function [
30‐
32]. According to our result, no difference was found in the incidence of side effects. However, delayed side effects such as delayed severe pneumonia could not be ruled out [
30].
In our analysis, the serum creatinine level of most patients in all eight studies ranged from 1.04 mg/ml to 2.6 mg/ml, among which one study [
20] did not state the exact data for Scr levels, one study [
22] included patients with the mean level of Scr over 2 mg/dl but below 2.6 mg/dl and the remaining studies included patients with mean Scr below 1.65 mg/dl. The eGFR (or creatine clearance rate) of all included patients were over 20 mL/min/1.73 m
2; but below 80 mL/min/1.73 m
2. There was limited variability in kidney function of patients in all eight studies, so we considered there to be no need for subgroup analysis according to the level of Scr. However, some factors should be taken into account, such as patient ethnicity and the mean proteinuria at baseline. Two studies whose participants were all Asian drew the conclusion that MMF was effective in lowering proteinuria, while two further studies with participants mostly of Caucasian ethnicity held the opposite opinion. These data imply that race may influence the efficacy of MMF treatment in IgA nephropathy. Clinical reports suggest that individuals of Asian/Pacific Island heritage are more likely to be affected by IgA nephropathy than other races and furthermore, IgA nephropathy may have a more severe disease course in certain Asian populations [
3,
33]. Unfortunately, with the limited information available from our included studies, we could not undertake subgroup analysis according to patient race.
Earlier systematic reviews [
12‐
14] had drawn the conclusion that no benefits were seen in IgA nephropathy patients treated with MMF. However, by using a more rigorous method, including subgroup analysis to resolve the high heterogeneity among those trials, we may draw a different conclusion. According to the results of subgroup analysis, duration of MMF therapy of less than 18 months may be beneficial. We also attempted to tabulate adverse events following MMF treatment. In addition, we compared the MMF and other immunosuppressive agents (CTX and LEF) with regard to their effectiveness and safety in IgA nephropathy.
However, our systematic review has some limitations. Most of the studies were single center studies with a limited number of patients. The follow-up period of these trials ranged from 6 to 36 months, which was not long enough to detect any long-term effects of MMF treatment in IgA nephropathy. For this reason, large, high-quality multicenter clinical trials with longer follow-up period are urgently needed.
Despite the limitations, our systematic review can provide some useful information for designing future trials. First, since evidence of the benefits of short term treatment with MMF is needed, studies comparing effects of long with short term treatment might be preferred in future. Second, trials with longer follow-up periods are required for the further study of the long term effects of MMF. Third, therapeutic effects comparing MMF with other immunosuppressive agents were reported in only a few studies and most of the patients were Asians. Therefore, large, multicenter clinical trials comparing the efficacy and safety of MMF and other immunosuppressive agents, particularly studies encompassing multiple ethnic groups, will be very valuable.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
CYY screened the abstract and full text, extracted data from selected articles, and drafted the manuscript. LYM, YSL and LY screened the abstract and full text, and extracted of data from selected articles. LY imported data and performed the statistical analysis. LM designed the study and drafted the manuscript. All authors read and approved the final manuscript.