Background
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and is the leading cause of end-stage renal disease (ESRD) [
1,
2]. According to Kidney Disease Improving Global outcomes (KDIGO) guideline, renin-angiotensin system inhibitor for IgAN patients with persistent proteinuria ≥0.5 g/d, and renin-angiotensin system inhibitor plus corticosteroid for IgAN patients with persistent proteinuria ≥1 g/d are recommended [
3]. However, up to 30% of the treated patients fail to respond to these therapies [
4,
5]. Therefore the lack of satisfactory therapeutic approach for IgAN still confuses physicians and researchers working in nephrology. The predominant character of IgAN is abnormal IgA1 deposition in mesangial area. Moreover, molecular and cellular interaction studies [
6], as well as genome-wide association studies [
7] revealed the autoimmune nature of this disease. These knowledges provide nephrologists a theoretical basis for the treatment of IgAN with immunosuppressive therapy.
Mycophenolate mofetil (MMF), a highly effective immunosuppressive agent, acts by releasing mycophenolic acid which leads to apoptosis of cytotoxic T-lymphocytes and reduction of antibody synthesis via selectively inhibits T- and B-lymphocyte proliferation [
8,
9]. In addition, growing clinical evidences have demonstrated that oral MMF is beneficial for IgAN secondary to systemic diseases, such as lupus nephritis [
10] and Henoch-Schonlein purpura nephritis [
11]. However, the application of MMF in treatment patients with primary IgAN is still uncertain. So far, few randomized controlled trails (RCTs) have studied the therapeutic effects of MMF on IgAN. The first RCT investigating the role of MMF in patients with IgAN was carried out by Chen et al. in 2002 [
12]. This study demonstrated that compared to prednisone, MMF was more effective in reducing proteinuria in patients with severe IgAN [
12]. Another RCT from China also claimed that corticosteroid-free MMF monotherapy was effective in decreasing proteinuria and ameliorating some of the abnormalities in IgAN [
13]. Moreover, a six-year follow-up of the same cohort also suggested a kidney survival benefit in patients treated with MMF monotherapy [
14]. In contrast to studies from Asians [
12‐
14], in a prospective placebo-controlled randomized study carried out in Belgium, patients were treated with restriction of salt intake, angiotensin converting enzyme inhibitors and either MMF or placebo [
15]. After 36 months of follow-up, however, no beneficial effects of MMF treatment could be demonstrated on renal function or proteinuria [
15]. One year later, similar result was reported in another double-blind, randomized, placebo-controlled trial from USA [
16]. Because of the inconsistency between these RCTs mentioned above, MMF was not recommended in treating IgAN by KDIGO guideline in 2012 [
3].
So far, more RCTs have provided the evidence for the effectiveness of MMF therapy in IgAN [
17‐
19]. Therefore re-evaluating the usage of MMF in treating patients with IgAN seems to be necessary. In a recent meta-analysis, both efficacy and safety of MMF regimen in treating IgAN were estimated [
20]. However, there were some limitations in this study. First, one trial included in this meta-analysis contained obviously incorrect data [
21]. Second, subgroup analysis by human race was not taken.
Considering these limitations may lead to unreliable conclusion, we carried out this update meta-analysis to comprehensively re-evaluate the efficacy and safety of MMF therapy in treating IgAN. In current meta-analysis, we added one new published RCT [
19], and removed one study with obviously incorrect data [
21].
Discussion
In a recent meta-analysis, the authors declared a relatively short course of MMF monotherapy might have favorable therapeutic effects such as remission rate and urinary protein reduction in IgAN [
20]. In fact, it is indeed hard to explain why the outcomes from long course of MMF monotherapy are not better than that from short course of MMF monotherapy. In present study, we performed an update meta-analysis by adding one new RCT [
19], and removing one RCT with unreliable data (in method part 19 and 14 participants were mentioned in MMF group and CTX group, respectively, but in result part 21 and 10 participants were mentioned in MMF group and CTX group, respectively) [
21]. We made main analysis by including all the eight studies at first, and then we divided the studies into two categories, corticosteroid-free, MMF monotherapy [
12,
13,
15,
16,
19] and corticosteroid plus MMF therapy [
17,
18,
25].
For all the eight studies, our main analysis found higher remission rates in MMF group compared to control group. However, these results were not consistence with the previous meta-analysis [
20]. Accumulating evidences have emerged and claimed that genetic factor contributes to the pathogeneses of IgAN [
26,
27]. Furthermore, the genetic risk score is highest in Asians, intermediate in Caucasians, and lowest in Africans [
28]. These genetic inconsistencies may explain why different human races have different responses to the same therapeutic regimen. Therefore, subgroup analysis by human race, which was not considered in previous meta-analysis [
20], were performed in our study. Despite moderate to extreme heterogeneities were found in all comparisons, the heterogeneities were reduced or even disappeared in subgroup analysis, suggesting different human races may be one of the sources of heterogeneities in present meta-analysis.
In subgroup analysis by human race, two RCTs from Asians [
12,
13] demonstrated obviously favorable outcomes, but two RCTs from Caucasians [
15,
16] and one RCT from mixed races [
19] failed to find significant differences between the two groups. Considering disease pathogenesis and the pharmacological effect of MMF, MMF is expected to play an important role in the treatment of IgAN. However, it was disappointed to see the negative results in Caucasians and mixed races from our present study. To be noticed, besides steroids and MMF, omega-3 fatty acid which was proven to be effective in treating IgAN [
29] was also used in the RCT from mixed races [
19]. Although all participants were administrated with omega-3 fatty acid during the entire trial, MMF treatment still could not significantly reduce proteinuria in patients with IgAN. The following reasons may explain the unexpected results. First, baseline proteinuria was severer in MMF monotherapy group than placebo group in one Caucasian RCT [
15]. As both a major outcome and a positive predictor, the non-comparative baseline urinary protein might lead to a negative result. Second, a study design of 2:1 randomization was used in above Caucasian RCT to maximize the sample size [
15]. Thus, the statistical power of this RCT was limited and we should interpret the result with caution. Third, in the other Caucasian RCT, baseline serum creatinine ranged from 2.2 mg/dl to 2.6 mg/dl [
16]. Since patient selection, in other words baseline renal function directly influences the therapeutic effects of MMF [
30], the advanced renal damage before MMF treating may cause non-favorable outcome. Fourth, all included five RCTs were single-center clinical trials, so the small sample size was another factor affecting the statistic power. Last but not least, corticosteroid recognized as the elementary medicine in treating IgAN [
31] was used in only one of the five trials [
12]. Maybe corticosteroid is basic and necessary for MMF to exert a therapeutic effect.
Immunosuppressive therapy like corticosteroid monotherapy and corticosteroid plus immunosuppressive agent therapy were well accepted in progressive IgAN treatment [
32,
33]. However, which immunosuppressive agent is more effective is still unclear. Corticosteroid plus CTX therapy has been reported to obtain favorable outcome as a classic regimen in treating patients with IgAN [
34,
35], while the adverse events caused by CTX can’t be ignored. Therefore, more safety immunosuppressive agents are needed. For corticosteroid plus MMF therapy studies, main analyses revealed better therapeutic effects in corticosteroid plus MMF group compared to corticosteroid plus other immunosuppressive agent group (CTX and LEF), including the remission rate and stable renal function. Our data were supported by previous studies [
14,
36]. All the three RCTs were from Asians, so we made subgroup analysis by therapy regimen instead of human race. Despite high to extreme heterogeneities were found in some comparisons, the heterogeneities disappeared in subgroup analysis, suggesting different therapy regimens may be another source of heterogeneities in our meta-analysis.
In subgroup analysis by therapy regimen, compared to corticosteroid plus CTX but not LEF therapy, corticosteroid plus MMF therapy had a more superior effect on IgAN outcomes, such as remission rate, reduction of urinary protein and stable renal function. Compared to CTX, the better efficacy of MMF on the basis of corticosteroid was found not only in mild IgAN [
25] but also in severe IgAN patients [
18]. Our result was consistent with another retrospective study from China. In this study, the effects of MMF and CTX were compared in treating proliferative pathological IgAN. Data showed that combination of MMF and prednisone therapy lead to a beret renal survival compared to that of prednisone with CTX [
37]. These results provided us evidence from evidence-based medicine. By removing one RCT with unreliable data [
21], our new results were similar with the previous meta-analysis [
20], suggesting the stability of this result. Both the efficacy and safety were comparative between corticosteroid plus MMF therapy and corticosteroid plus LEF therapy [
17]. However, this conclusion was based on only one RCT, therefore, more RCTs evaluating corticosteroid plus LEF therapy are needed.
Besides human race and therapy regimen, renal histopathology was also an important factor affecting the efficacy of immunosuppressive therapy. For all the eight included studies, five studies had renal histologic assessment [
13,
16,
18,
19,
25]. Although the degree of histologic damage at baseline between MMF group and control group was comparable, no study discussed the impact of renal pathology on therapeutic effects. In an observed study conducted by a Chinese group, the efficacy of MMF plus prednisone in treating Children with steroid-resistant IgAN was investigated. All biopsy samples were scored according to the Oxford classification. It was suggested that MMF plus prednisone therapy was effective in steroid-resistant children. However, unsatisfactory outcome was found in children with tubular atrophy/interstitial fibrosis [
38].
Our main analysis of adverse events revealed that MMF monotherapy seemed to have a higher side effect rate because of the marginal difference between the two groups (
P = 0.03). By restudying the included RCTs, we found only one RCT from Asians reported a significant higher side effect rate in MMF monotherapy group [
13]. The main adverse events in MMF monotherapy group were gastrointestinal symptoms (8/81), infection (4/81) and blood system changes (3/81). Considering the marginal differences and small number of participants in this meta-analysis, to convince our result, more RCTs with big sample size are requested. In contrast to the above results, main analysis of adverse events showed that side effect rate in corticosteroid plus MMF group was much lower than that in corticosteroid plus other immunosuppressive agent group. And subgroup analysis by therapeutic regimen confirms the main analysis results. Except for infection, gastrointestinal symptoms and blood system changes, irregular menstruation (5/80), liver damage (3/80), blood system damages (3/80) and hair loss (3/80) in corticosteroid plus CTX regimen group were reported.
Our present meta-analysis has some limitations. First, not all included studies were high quality RCTs. Second, it will takes 15–30 years to progress to ESRD from IgAN onset [
39]. Thus, with the follow-up period ranged from six to thirty-six months in these RCTs, it is difficult to observe obvious changes in kidney survival situation. Third, the majority of studies were from Asian patients, studies from other human races are needed.