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REVIEW ARTICLE
Year : 2020  |  Volume : 23  |  Issue : 4  |  Page : 437-449

Immunosuppressive agents in the treatment of IgA nephropathy: A meta-analysis of clinical randomized controlled literature


1 Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai, China
2 Department of Nephrology, Former Chief of Nephritic Department, Zhong Shan Hospital, Fudan University Shanghai Medical College, Shanghai, China

Date of Submission09-Mar-2018
Date of Acceptance17-Apr-2019
Date of Web Publication4-Apr-2020

Correspondence Address:
Prof. Xuezhong Gong
Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai 200071
China
Zhaolong Wu
Department of Nephrology, Former Chief of Nephritic Department, Zhong Shan Hospital, Fudan University Shanghai Medical College, Shanghai, 200065
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_112_18

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   Abstract 


IgA nephropathy (IgAN) is the most common form of glomerulonephritis in the world. Immunosuppressive therapy has been widely used in IgAN patients at home and abroad. The present meta-analysis aimed to assess the efficacy and safety of different immunosuppressive agents in patients with biopsy proven IgAN, in order to provide guidance for the clinical treatment of IgAN treatment options. We conducted a meta-analysis of the published randomized controlled trials (RCTs). PubMed, EMBASE, Web of Science, Cochrane Library, Medline, WanFang, Weipu, and CNKI were searched for relevant RCTs published between 2000 and December 2017. Data were analyzed with the random effects model using Review Manager5.3 to evaluate the effect of immunosuppressive agents on IgAN. 52 RCTs were involving 2,930 patients were included in the review. Compared with steroids, immunosuppressive agents, including acetazolamide (AZA) [complete response (CR)/partial response (PR); relative risk (RR), 5.92; 95% confidence interval (CI) 3.07–11.44; P< 0.00001], leflunomide (LEF) (CR/PR; RR, 1.63; 95% CI,1.22–2.17; P = 0.0008), mycophenolate mofetil (MMF) (CR/PR; RR, 1.59; 95%CI, 1.02–2.49; P = 0.04), cyclophosphamide (CTX) (CR/PR; RR, 3.39; 95%CI, 1.03–11.14; P = 0.04), and Tacrolimus (TAC) (CR/PR; RR, 1.72; 95%CI, 0.99–2.96; P = 0.05) resulted in increased partial or complete proteinuria remission. There was no significant difference in the total effective rate between MMF and Placebo (CR/PR; RR, 0.92; 95% CI, 0.33–2.56; P = 0.87). Compared with CTX, MMF showed higher effectiveness (CR/PR; RR, 3.32; 95% CI, 1.83–6.01; P< 0.0001) and LEF showed higher effectiveness (CR/PR; RR, 1.85; 95% CI, 1.17C–2.92; P = 0.009) with a lower incidence of adverse events. The results showed that immunosuppressive agents are a promising strategy and should be investigated further. MMF is the safest, the best therapeutic result and the least side effects than the other immunosuppressive agents.

Keywords: IgA nephropathy, Immunosuppressive agents, meta-analysis, the clinical randomized controlled literature


How to cite this article:
Zheng J, Gong X, Wu Z. Immunosuppressive agents in the treatment of IgA nephropathy: A meta-analysis of clinical randomized controlled literature. Niger J Clin Pract 2020;23:437-49

How to cite this URL:
Zheng J, Gong X, Wu Z. Immunosuppressive agents in the treatment of IgA nephropathy: A meta-analysis of clinical randomized controlled literature. Niger J Clin Pract [serial online] 2020 [cited 2020 Sep 28];23:437-49. Available from: http://www.njcponline.com/text.asp?2020/23/4/437/281914




   Introduction Top


It has been demonstrated that IgAN is the most frequently occurring primary glomerulonephritis worldwide.[1] It is causing end-stage renal disease (ESRD) in up to 15–20% of patients within 10 years from the apparent onset of disease and in up to and 30-40% within 20 years.[2],[3],[4],[5],[6] The variability is on account of strategy for biopsy of patients suspected of having IgAN and by the severity of disease at the time of definitive biopsy diagnosis of IgAN.[7],[8] No specific treatment has been established, but many approaches have been researched. The mechanisms involved in the pathogenesis of this disease have remained unclear.[9],[10] The factors genetic and environmental were influenced susceptibility to IgAN and risk of disease progression. The use of immunosuppressants is supported by experimental insights into IgAN pathogenesis that suggest an autoimmune component in disease development. Experimental insights into IgAN pathogenesis was supported the use of immunosuppressants that suggest an autoimmune component in disease development.[11] Many treatments have been attempted in the past two decades; however, no specific treatment has been established with wide variations in current practice.[12],[13],[14] In the absence of a thorough understanding of its pathogenesis, a consensus on optimal treatment has not yet to be established. The results of some clinical trials showed that immunosuppressive therapy shall improve the prognosis of patients with IgAN and reduce the risk of ESRD. In order to find optimal regimens of immunosuppressive agents in patients with IgAN, we performed a systematic review of these treatments to aid healthcare providers in managing this condition. This study summarizes currently available randomized and quasi randomized controlled trial evidence on the effect of immunosuppression for the treatment in patients with IgAN. The commonly immunosuppressive agents used for IgAN immunosuppressive therapy include immunosuppressive agents: AZA, MMF, TAC, LEF, and CTX.[15],[16],[17],[18] There are increasing attention has been paid to the role of immunosuppressive agents in the treatment of IgAN. The present report aimed to generate a meta-analysis from the most up-to-date studies regarding the safety and efficacy of various immunosuppressive therapeutic strategies for the treatment of patients with IgAN, in order to provide comprehensive current information to nephrologists to aid decision making. China has the largest population worldwide, and has a high incidence of IgAN. In order to exclude interferences that may be due to the ethnicity of patients, the present meta-analysis was performed using studies involving Chinese patients exclusively.


   Materials and Methods Top


Search strategy

Numerous databases were searched for eligible RCTs, including PubMed (2000–2017), Embase (2000–2017), Web of Science (2000–2017), Cochrane Library (2000–2017), Wanfang (2000–2017), Weipu (2000–2017), and CNKI (2000–2017), without language restriction. References in Medline-cited studies were reviewed to identify additional reports not indexed by Medline (2000–2017). The following key words and subject terms were used: IgA nephropathy, IgA nephritis, immunoglobulin A nephropathy, IgA glomerulonephritis, Berger's disease, mycophenolate mofetil (MMF), Azathioprine (AZA), Leflunomide (LEF), tacrolimus (TAC), Cyclophosphamide (CTX), clinical randomized controlled literature, and immunosuppressive therapy. Only RCTs published in Chinese and English were considered to be eligible. Reference lists from identified articles were also searched. According to the inclusion criteria, the title and abstract of the search results were analyzed by two authors.

Inclusion criteria

The following inclusion criteria were used in the present meta-analysis:(i) The study was an RCT, which was published by Immunosuppressive agents in the treatment of IgA nephropathy; (ii) diagnosis of IgAN was performed via renal biopsy; (iii) Get complete data from the full text data, data overlap of the literature after discussion with the selection of the best; and (iv) the study was published in English or Chinese.

Exclusion criteria

Studies were excluded if they: (i) were designed without randomization; (ii) use of traditional Chinese medicine; (iii) Incomplete data; (iv) review, case reports and summary of the meeting.; (v) secondary IgA nephropathy, including diabetes Kidney disease, hepatitis B virus-associated nephritis, tumor combined with IgAN, et al.; (vi) animal test; and (vii) severe liver and kidney damage, combined with lactating women or pregnant women taking other immunosuppressive agents.

Data extraction

Each trial was independently extracted from each study by two investigators using a predesigned review from the selected studies for this purpose. Data were extracted from all included trials in terms of patient characteristics of the study sample, doses, and modalities of treatment, the following information was included: first author, unit of each study, journal, year of publication, country of publication; demographics, patient characteristics of the study sample; follow-up time, the number of cases, interventions, including baseline value of impairment renal function and type of immunosuppressive agents, dose, and usage; and the methodology of the RCTs and the following outcomes: proteinuria, serum creatinine and serum albumin levels, and the type of outcome (complete remission, remission, and total effective rate) were recorded. The longest period of follow-up was be used if an outcome was reported at more than one time point for a single study. All reported data on adverse events of treatment were also collected.

Assessments of methodological quality

The respective qualities of the RCTs were independently assessed, using the “Bias Risk Assessment” of the Cochrane Systematic Review developed. The project includes the following: (1) what the method of random allocation was be used, the method was correct or error; (2) whether the allocation scheme was hidden; (3) whether used blindness; (4) the completeness of the results data; (5) the results of the selective report; (6) withdrawals and dropouts; and (7) the other sources of bias.

Statistical analysis

Statistical analyses were performed using Cochrane RevMan5.3. The results were analyzed by using the relative risk (RR) measure for dichotomous outcomes, and weighted mean differences, for continuous outcomes, with 95% confidence intervals (95%CI). Heterogeneity among the included trials was analyzed using the heterogeneity Q statistic test. P = 0.05 was regarded as the critical value for homogeneity. The fixed-effect model weighted by the Mantel–Haenszel method was used, followed by a test of homogeneity. If the hypothesis of homogeneity was rejected (P < 0.05), the DerSimonian and Laird method in the random effects model was used for meta-analysis. If there is heterogeneity exists, subgroup analysis may lead to heterogeneity. We shall exclude the heterogeneity of clinical and methodological methods, if the heterogeneity is still exist, the random effect model was used for the combined analysis. Heterogeneity of treatment effects between studies was investigated visually by examination of plots and statistically by using the I2 statistics.


   Results Top


Trial flow and study characteristics

The combined search identified 3,484 articles, of which 1,012 English and 2,472 Chinese. 3,384 patients were included during the initial review. After discarding a number of duplicates retrieved by individual searches and reviewing all titles and abstracts, 3,414 studies were excluded because they were not RCTs, or were not meant to investigate any of the outcomes of interest to this study, or were animal or basic research studies, along with a number of experiments involving only corticosteroids. A total of 50 articles were reviewed in full text to further assess their eligibility. Overall, 52 RCTs (19–68), Including 2,930 patients, were included in the present meta-analysis [Figure 1]. The following comparisons were analyzed: AZA (or plus steroid) vs. steroid therapy alone (n = 4); MMF (or plus steroid) vs. steroid (n = 6); MMF (or plus steroid) vs. placebo (n = 3); MMF (or plus steroid) vs. CTX (or plus steroid) (n = 5); LEF (or plus steroid) vs. steroid (n = 18); LEF (or plus steroid) vs. CTX (or plus steroid) (n = 7); CTX (or plus steroid) vs. steroid (n = 2); and TAC (or plus steroid) vs. steroid (n = 7). In 50 studies, immunosuppressive agents were involved in the comparison. The characteristics of the included RCTs are shown in [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6] [Table 7]. The details are as follows: interventions, design and number of groups, study period, concomitant drugs, adverse reactions, and baseline characteristics of populations.
Figure 1: Flow diagram outlining the number of citations identified, retrieved, and included in the final meta-analysis

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Table 1: Characteristics of the participants, interventions, comparisons, and outcomes in the included AZA vs. steroid

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Table 2: Characteristics of the participants, interventions, comparisons and outcomes in the included LEF vs. steroid

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Table 3: Characteristics of the participants, interventions, comparisons, and outcomes in the included LEF vs. CTX

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Table 4: Characteristics of the participants, interventions, comparisons, and outcomes in the included MMF

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Table 5: Characteristics of the participants, interventions, comparisons, and outcomes in the included MMF vs. CTX

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Table 6: Characteristics of the participants, interventions, comparisons and outcomes in the included CTX vs. steroid

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Table 7: Characteristics of the participants, interventions, comparisons, and outcomes in the included TAC vs. steroid

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Effects of interventions

Trials of AZA (or plus steroid) vs. steroid treatment

The comparison of the efficacy and safety of the AZA (or plus steroid) vs. steroid in the therapy of IgAN patients included four RCTs (19–22) with 228 patients. AZA (1.5–2 mg/kg/day) was orally administered for 6–12 months. Prednisolone (0.8–1.0 mg/kg/day) was administered for 4–8 weeks, and subsequently tapered off within 1 year. Compared with the steroid therapy alone, patients receiving AZA demonstrated significantly increased CR/CR proteinuria remission rates [CR/PR; RR, 5.92; 95% CI, 3.07–11.44; P < 0.00001] [Figure 2].
Figure 2: Complete/partial proteinuria remission rates in randomized controlled trials comparing AZA (or plus steroid) treatment with steroid treatment alone in patients with IgAN. AZA, acetazolamide; MH, MantelHaenszel; CI, confidence interval

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Trials of LEF (or plus steroid) vs. steroid treatment

We identified 18 RCTs (23–40) that had enrolled a total of 1,096 patients compared LEF (or plus steroid) with steroid therapy alone. LEF (20–60 mg/day) was orally administered for 3 days, tapered, and subsequently reduced to 20 mg/day for 3 months. Patients receiving LEF demonstrated significantly increased [CR/PR; RR, 1.63; 95% CI, 1.22-2.17; P = 0.002] [Figure 3] as compared with the steroid therapy alone.
Figure 3: Complete/partial remission proteinuria rates in randomized controlled trials comparing LEF (or plus steroid) treatment with control treatment in patients with IgAN. LEF, leflnomide; CTX, cyclophosphamide

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Trials of LEF (or plus steroid) vs. CTX (or plus steroid) treatment

About 7 RCTs (41–47) involving 414 patients compared LEF (or plus steroid) with CTX (or plus steroid). LEF (40–50 mg/day) was orally administered for 3 days, reduced to 10–20 mg/day for 3 months, and subsequently tapered. As compared with CTX, LEF was significantly more effective in inducing remission (CR/PR; RR, 1.85; 95% CI, 1.17–2.92; P = 0.009) [Figure 3].

Trials of MMF (or plus steroid) vs. steroid treatment

About 6 RCTs (48–53) that had enrolled a total of 337 patients compared MMF (or plus steroid) with steroid therapy alone. MMF (1.0–2.0 g/day) was orally administered for 3–6 months, and subsequently tapered. MMF treatment lasted for 8–12 months. Overall, according to this analysis, MMF treatment induced a greater therapeutic result when compared with steroid group (CR/PR; RR, 1.59; 95%CI, 1.02–2.49; P = 0.04) [Figure 4].
Figure 4: Complete/partial proteinuria remission rates in randomized controlled trials comparing MMF (or plus steroid) treatment with control treatment in patients with IgAN. MMF, mycophenolate mofetil; CTX, cyclophosphamide

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Trials of MMF (or plus steroid) vs. placebo treatment

Compared MMF (or plus steroid) with placebo included 3 RCTs (54–56) enrolled 99 patients. MMF (1.0–2.0 g/day) was orally administered for 3–6 months, and gradually tapered thereafter. MMF treatment lasted for 12–36 months. There was no significant difference in the total effective rate between MMF and Placebo (CR/PR; RR, 0.92; 95% CI, 0.33–2.56; P = 0.87) [Figure 4].

Trials of MMF (or plus steroid) vs. CTX (or plus steroid) treatment

About 5 RCTs (52, 57–60) enrolled 272 patients compared MMF (or plus steroid) with CTX (or plus steroid). MMF (1.0–1.5 g/day) was orally administered for 6 months, and gradually tapered thereafter. The immunosuppressive treatment lasted for 8–12 months. Compared to CTX, MMF showed higher effectiveness (CR/PR; RR, 3.32; 95% CI, 1.83–6.01; P < 0.0001) with a lower incidence of adverse event [Figure 4].

Trials of CTX (or plus steroid) vs. steroid treatment

The comparison of the efficacy and safety of the in the therapy of IgAN patients included 2 RCTs (52, 61) with 126 patients compared CTX (or plus steroid) with steroid therapy alone. CTX (0.5–0.75 g/m2/4 weeks) was orally administered for 6 months, and subsequently tapered. CTX treatment lasted for 12 months. CTX demonstrated a marked advantage on CR/PR proteinuria remission, as compared with the steroid therapy (CR/PR; RR, 3.39; 95%CI, 1.03–11.14; P = 0.04). [Figure 5]
Figure 5: Complete/partial proteinuria remission rates in randomized controlled trials comparing CTX treatment with steroid treatment alone in patients with IgAN. CTX, cyclophosphamide

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Trials of TAC (or plus steroid) vs. steroid treatment

[Figure 6] shows the meta-analysis of the efficacy and safety between TAC and steroid. About 7 RCTs (62–68) involving 358 IgAN patients. TAC (0.075–0.08 mg/kg) was orally administered for 6 months and gradually tapered thereafter. TAC treatment lasted for 6–24 months. Compared to steroid, TAC showed higher effectiveness (CR/PR; RR, 1.72; 95%CI, 0.99–2.96; P = 0.05) with a lower incidence of adverse event [Figure 6].
Figure 6: Complete/partial proteinuria remission rates in randomized controlled trials comparing TAC treatment with steroid treatment alone in patients with IgAN. TAC, tacrolimus

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Side effects of treatment

Although it is challenging to statistically analyze the side effects in a single comparison, and the number of side effects for each agent were recorded. For AZA treatments versus steroid alone, two studies of four RCTs[19],[20] recorded adverse effects of treatment. Adverse events were reported in two studies, including the following:[21],[22] myelosuppression (n = 6; 5.4%), liver dysfunction (n = 2; 1.8%), digestive symptoms (n = 3; 2.7%), infection (n = 1; 0.9%), and leukopenia (n = 4; 3.6%). During MMF treatment versus steroid alone, 10 patients (10/335, 3.0%) demonstrated digestive symptoms; whereas a further 6 patients (1.8%) exhibited elevated liver enzymes. A total of 14 patients (4.2%) demonstrated infective episodes, including 9 severe pulmonary infections and 5 urinary tract infections; a total of 3 patients treated with MMF demonstrated decreased hemoglobin, 3 patients exhibited moon face, and 16 patients (4.8%) demonstrated Cushing syndrome.

In the MMF (or plus steroid) vs. CTX (or plus steroid) comparison, 4 patients (4/272,1.5%) treated with MMF demonstrated herpes zoster, and 2 patients demonstrated infective episodes; whereas 12 patients (4.4%) receiving CTX demonstrated digestive symptoms; furthermore, 12 patients (4,4%) receiving CTX, respectively, herpes zoster, leukocytopenia, and elevated liver enzymes; 3 patients demonstrated pneumonia and irregular menstruation. The MMF group had lower frequency and lesser degree of side effects than the CTX group. There was no significant difference in the side effects between MMF group and placebo group.

A total of 88/1,132 patients (7.8%) treated with LEF or plus steroid) vs. CTX steroid recorded adverse effects of treatment. A total of 23/1,132 patients (2.0%) treated with LEF demonstrated elevated liver enzymes, and a further 14 patients (1.2%) exhibited digestive symptoms; 28 patients (2.5%) developed infection, and 6 patients (0.6%) developed alopecia. Zhang Yan[29] has two patients who received LEF withdrew from the trial because of severe granulocytopenia and liver damage.

In the LEF (or plus steroid) vs. CTX (or plus steroid)' comparison, 12 and 26 patients treated with LEF and CTX, respectively, demonstrated liver dysfunction; 7 and 37 patients receiving CTX and LEF demonstrated digestive symptoms; 8 and 9 patients receiving CTX and LEF developed alopecia; 1 and 19 patients receiving CTX and LEF demonstrated aleucocytosis; 1 and 5 patients receiving CTX and LEF developed pneumonia; 3 and 6 patients treated with LEF and CTX demonstrated pulmonary infection. Furthermore, 2 patients receiving CTX developed herpes-zoster virus infection, 12 patients demonstrated irregular menstruation; 1 patients developed ovarian atrophy. Therefore, the LEF group had lower frequency and lesser degree of side effects than the CTX group.

During TAC treatment versus steroid alone, whereas a further 10 patients (10/353, 2.8%) exhibited elevated liver enzymes. A total of nine patients (2.5%) demonstrated elevated blood sugar; eight patients (2.3%) demonstrated impaired glucose tolerance; four patients demonstrated newly diagnosed diabetes; three patients exhibited elevated serum creatinine; four patients demonstrated tremor, and three patients demonstrated uric acid. Two patients demonstrated pulmonary infection and elevated blood pressure.

Publication bias and sensitivity analysis

Publication bias was examined using funnel plots, which is shown in [Figure 7]. The symmetric distribution suggests that there was no publication bias in these studies.
Figure 7: Funnel plot analysis of the complete and partial rates of proteinuria remission in the four comparison groups. AZA, acetazolamide; MMF, mycophenolate mofetil; LEF, leflunomide; CTX, cyclophosphamide; TAC, tacrolimus; SE, standard error; OR, odds ratio

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   Discussion Top


IgAN is a disease that affects patients worldwide. The immunological mechanisms associated with the development and progression of IgAN suggest that immunosuppressive therapies may have a beneficial role in the treatment of active IgAN and associated proteinuria.[69] Active glomerular lesions can be reversed by immunosuppressive treatment in patients with IgAN. The reversal is accompanied by improvement in proteinuria and hematuria.[70] In literature, actve IgAN should be defined: (1) urinary protein ≥1.0 g/24 h, (2) blood creatinine progressively elevated, (3) recurrent hematuria. The use of Immunosuppressive agents in patients with IgA nephropathy can reduce the risk of ESRD statistics the risk of ESRD. In the present meta-analysis, a comprehensive literature search with limited restrictions in publication language was performed in order to compare the efficacy and safety of immunosuppressive agents such as CTX, LEF, MMF, and AZA, which are widely used in the treatment of Chinese patients with IgAN.

The most effective and safety of immunosuppressive agents was performed to compare in the treatment patients with IgAN in the present meta-analysis, in order to provide evidence-based evidence for clinical practice. In the present meta-analysis, a total of 3,026 patients from 50 studies (19–68) were included. As too few studies reported long-term outcomes, the present meta-analysis only reviewed short-term parameters in order to evaluate the efficacy of the respective treatments, including the total effective rate (complete and partial) of the participants. Complete remission of proteinuria was defied as <0.3 g/day and serum albumin >35 g/L with normal renal function. In comparison with steroid treatment alone, the patients demonstrated an improved treatment response to AZA administration. Notably, the patients demonstrated more effects response to AZA administration, as compared with steroid treatment alone. However, in comparison with steroid treatment alone, the use of MMF, LEF, CTX, and TAC all did result in a significant increased remission rates. There was no significant difference in the total effective rate between MMF and Placebo. Compared with CTX, MMF showed higher effectiveness and LEF showed higher effectiveness with a lower incidence of adverse events. The above results show that the use of immunosuppressive agents may be better than steroid/other nonimmunosuppressive treatment is strongly proven. MMF in the treatment of IgAN is the most safest, the best therapeutic result, and the least side effects as compared to placebo/other immunosuppressive treatment. Steroid alone in the treatment of IgA nephropathy have more side effects. The side effects of the different immunosuppressive treatments individually and in combination have been inadequately reported in the available randomized trials. The available studies tend to report favorable or surrogate outcomes and have a thorough reporting of side effects of treatment. Hannah Beckwith et al.[71] demonstrated that 18 patients in treatment with MMF alone with IgAN repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. Agnes Hacki et al.[72] reviewed the experimental nontransplant glomerular disease models on the mechanisms of MMF therapy. The experiment shows that MMF was an excellent treatment option in many immunologic glomerulopathies, because of its immunosuppressive properties. The immunosuppressive properties has a remarkable effect on nonimmune cells and counteracts the proliferation of mesangial cells, expansion of mesangial matrix, and foot-process effacement of podocytes combined with a low systemic toxicity.

MMF is relatively selective for lymphocytes and inhibits antibody production by B-cells more than other immunosuppressants.[73] MMF also has a variety of nonimmune effects, such as those on glomerular cells, which may contribute to its clinical efficacy. Several studies have looked at the actions of MMF on mesangial cells, which may come down to inflammatory proliferative glomerulopathies. MMF inhibited mitogen-induced rat mesangial cell proliferation, and it also inhibited human mesangial cell proliferation. Case series suggest that MMF may be effective in reducing proteinuria in a variety of glomerular diseases, including IgAN.

In conclusion, our meta-analysis showed that AZA, MMF, LEF, CTX, and TAC agents seem to be beneficial for the remission of proteinuria in patients with IgAN. In addition, as compared with AZA, MMF, LEF, CTX, and TAC, MMF administration demonstrated a lower incidence of adverse reactions. Furthermore, the results of the present meta-analysis support the need for a large, high-quality multicenter trial in order to ascertain whether immunosuppressive treatments may be effective in a broad population of patients with high-risk IgAN, specifically to determine their effects in kidney failure. Using MMF is a promising strategy and should be investigated further. Current evidence-based practice guidelines should continue to emphasize MMF as the primary pharmacological therapy for patients with IgAN.

Acknowledgements

The present meta-analysis was supported by the National Natural Science Foundation of China (Grant no. 81573936 and Grant no. 81373617). The authors of the present study acknowledge Professor Xuezhong Gong of shanghai municipal hospital of traditional chinese medicine, shanghai university of traditional Chinese medicine and Professor Zhaolong Wu of Zhong shan Hospital, Fudan University Shanghai Medical College for their support in data analyses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. Am J Kidney Dis 2001;38:728-35.  Back to cited text no. 1
    
2.
D Amico G. Natural history of idiopathic IgA nephropathy: Role of clinical and histological prognostic factors. Am J Kidney Dis 2000;36:227-37.  Back to cited text no. 2
    
3.
Alamartine E, Sabatier JC, Guerin C, Berliet JM, Berthoux F. Prognostic factors in mesangial IgA glomerulonephritis: An extensive study with univariate and multivariate analyses. Am J Kidney Dis 1991;18:12-9.  Back to cited text no. 3
    
4.
Bogenschütz O, Bohle A, Batz C, Wehrmann M, Pressler H, Kendziorra H, et al. IgA nephritis: On the importance of morphological and clinical parameters in the long-term prognosis of 239 patients. Am J Nephrol 1990;10:137-47.  Back to cited text no. 4
    
5.
Schena FP. Immunoglobulin A nephropathy with mild renal lesions: A call in the forest for the physicians and nephrologists. Am J Med 2001;110:499-500.  Back to cited text no. 5
    
6.
Rostoker G, Desvaux-Belghiti D, Pilatte Y, Petit-Phar M, Philippon C, Deforges L, et al. Immunomodulation with low-dose immunoglobulins for moderate IgA nephropathy and Henoch-Schönlein purpura. J Nephron 1995;69:327-34.  Back to cited text no. 6
    
7.
Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nat Rev Dis Primers 2016;2:16001.  Back to cited text no. 7
    
8.
Lai KN. Recent advances in IgA Nephropathy. World Scientific 2009.  Back to cited text no. 8
    
9.
Lai KN. Pathogenesis of IgA nephropathy. Nat Rev Nephrol 2012;8:275-83.  Back to cited text no. 9
    
10.
Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol 2011;22:1785-91.  Back to cited text no. 10
    
11.
Rauen T, Floege J. Inflammation in IgA nephropathy. Pediatr Nephrol 2017;32:2215-24.  Back to cited text no. 11
    
12.
Floege J, Eitner F. Present and future therapy options in IgA nephropathy. J Nephrol 2005;18:354-61.  Back to cited text no. 12
    
13.
Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005;16:2088-97.  Back to cited text no. 13
    
14.
Samuels JA, Strippoli GF, Craig JC, Ruospo M, Samuels JA, Molony DA, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2003;4:CD003965.  Back to cited text no. 14
    
15.
Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose deficient hinge region and antiglycan antibodies. J Clin Invest 1999;104:73-81.  Back to cited text no. 15
    
16.
Mestecky J, Suzuki H, Yanagihara T, Moldoveanu Z, Tomana M, Matousovic K, et al. IgA nephropathy: Current views of immune complex formation. Contrib Nephrol 2007;157:56-63.  Back to cited text no. 16
    
17.
Herr AB, Ballister ER, Bjorkman PJ. Insights into IgA-mediated immune responses from the crystal structures of human Fc RI and its complex with IgA1-Fc. Nature 2003;4239:614-20.  Back to cited text no. 17
    
18.
Floege J. The pathogenesis of IgA nephropathy: What is new and how does it change therapeutic approaches?.; Am J Kidney Dis 2001;58:992-1004.  Back to cited text no. 18
    
19.
Huang S, Luo FZ. The treatment of benazepril combined with azathioprine for the IgA nephropathy. International Medicine and Health Guidance News2009;19:57-84.  Back to cited text no. 19
    
20.
Kuang B. Effect of benazepril combined with azathioprine on IgA nephropathy. China Modern Doctor 2009;15:6-7.  Back to cited text no. 20
    
21.
Li YN, An ZM. Curative effect analysis of Benazepril combined with azathioprine on IgA nephropathy along with the amount of proteinuria. Hua Bei Mei Tan Yi Xue Yuan Xue Bao 2011;4:471-2.  Back to cited text no. 21
    
22.
Xu H, Zhou YJ. Azathioprine and prednisone, valsartan Clinical observation on treatment of IgA nephropathy. Zhe Jiang Yi Xue 2013;3:227-9.  Back to cited text no. 22
    
23.
Lou TQ, Wang C, Chen ZJ, Shi C, Tang H, Liu X, et al. Randomised controlled trial of leflunomide in the treatment of immunoglobulin A nephropathy. Nephrology 2006;11:113-6.  Back to cited text no. 23
    
24.
Zhang XZ, He YC, Lou Q, Yang TC, Li XG. Treatment of IgA nephropathy with leflunomide: Aprospective multicenter controlled clinical trial. Chinese Journal of Practical Internal Medicine 2008;28:110-112.  Back to cited text no. 24
    
25.
Cao LO, Ni ZH, Yan YC, Fang Y, Zhang WM, Mou S, et al. Leflnomide in combination with medium/low dose of prednisolone in treatment of progressive IgA nephropathy. Shanghai Medical Journal 2009;9:791-5.  Back to cited text no. 25
    
26.
Fu Q, Wang ZH, Guo Weifeng. Effects of leflunomide combined with hormone therapy for IgA nephropathy. Shanxi Medical Journal 2009;3:351-3.  Back to cited text no. 26
    
27.
Yang FY. A controlled study on the effect of leflunomide in treatment of IgA nephropathy. China Practical Medicine 2009;22:17-19.  Back to cited text no. 27
    
28.
Zhang Y. Effiacy ofleflnomide combined with prednisone in the treatment of advanced IgA nephropathy. Academic Journal of Guangzhou Medical College 2010;23:82-5.  Back to cited text no. 28
    
29.
Li T, Feng AQ, Liu YZ, Wu X, Huang Y, Chen Y, et al. Study on effect of leflnomide combined with glucocorticoid in treatment of progressive IgA nephropathy. ModernJournal of Integrated Traditiona Chinese and Western Medicine 2011;1:13-5.  Back to cited text no. 29
    
30.
Pu L, Chen Y, Sun D. Effiacy of benazepril combined with leflnomide in treatment of IgA nephropathy. Jiangsu Medical Journal 2011;11:1277-9.  Back to cited text no. 30
    
31.
Chang J, Song XQ, Zhang WJ, Qiu XJ, Fang Z. Effect of urinary transforming growth factor-p1 (TGFIH) on Leflunomide in combination with prednisolone in treatment of IgA nephropathy. Chinese Journal of Misdiagnostics 2012;12:2818-20.  Back to cited text no. 31
    
32.
Wu SQ, Wang JS. Effects of leflunomide plus glucocorticoids on IgA nephropathy. Journal of Chinese Practical Diagnosis and Therapy 2014;28:504-506.  Back to cited text no. 32
    
33.
Peng K, Hong DQ, Zou YR, Zhang P, Zhang YL, Li GS, et al. Combined use of leflunomide and steroids for lgA nephropathy. Journal of Clinical Nephrology 2014;14:86-89.  Back to cited text no. 33
    
34.
Wang XL, Zhang YG, Zhang J. Treatment of IgA nephropathy and effect on IgA-fibronection with leflunomide and prednisone. J Med Health 2014;22:2-3.  Back to cited text no. 34
    
35.
Yang YQ, Chang XD, Cheng ML, Yang YJ, Zhao M. Effects of leflunomide combined with glucocorticoid in the treatment of progressive IgA nephropathy and its influence on VCAM-1 level. Progress in Modern Biomedicine 2016;16:2134-2137.  Back to cited text no. 35
    
36.
Sheng SZ, Yang ZM, Cai JY, Xie QH, Hu YY, Suan LY, et al. Clinical eficacy and safety for leflunomide and dehydrocortisone in the treatment of immunoglobulin A nephropathy. Chin J Clin Pharmacol 2016;32:6-8.  Back to cited text no. 36
    
37.
Min LL, Zhang MF, Che XJ, Mou S, Cao LO, Wang, et al. Leflunomide combined with medium/low dose corticosteroids vs full dose of corticosteroids in treatment of IgA nephropathy. Chin J Nephrol 2016;32:721-727.  Back to cited text no. 37
    
38.
Li X. Clinical study on leflunomide combined with prednisone in treatment of Nephrotic syndrome as the mian manifestation of IgA nephropathy. China Health Standard Management 2016;7:81-82.  Back to cited text no. 38
    
39.
Li DF, Ren JX. Clinical observation of prednisone aetate combined with leflunomide in the treatment of IgA nephropathy. China academic journal electronic publishing house 2016;27:1118-20.  Back to cited text no. 39
    
40.
Lu LM, Wang Q, Cao L, Zhou W, Yuan J, Zhang M, et al. Comparison of combined leflunomide and low-dose corticosteroid therapy with full-dose corticosteroid monotherapy for progressive IgA nephropathy. Oncotarget 2017;8:48375-84.  Back to cited text no. 40
    
41.
He Y. A clinical study of leflunomide plus predenisone on IgA nephropathy (nephrotic syndrome type). Natural Science Edition 2008.  Back to cited text no. 41
    
42.
Wang YB, Zhang L, Lu S. Leflunomide therapy versus cyclophosphamide treat ment in patients with severe children IgA nephropathy. China Modern Doctor 2009;47:11-2.  Back to cited text no. 42
    
43.
Zhong SH, Chen GQ. Comparison study of leflunomide and cydophosphamide on IgA nephropathy (Nephritis Syndrome Type). Journal of North China Coal Medical College 2011;5:593-4.  Back to cited text no. 43
    
44.
Su X, Bao BY, You XQ, Li GF, Liu T. Comparison of effect of leflunomide and cydophosphamide on IgA nephropathy (Haas stage III~IV). Modern Practical Medicine 2013;25:851-3.  Back to cited text no. 44
    
45.
Zou YR, Li GS, Zhang P, Wang W, Liao CZ, Wang L. Cyclophosphamide versus leflunomide combined with prednisone respectively in treatment of chronic progressive IgA. Chinese Journal of Integrated Traditional and Western Nephrology 2013;14:1059-61.  Back to cited text no. 45
    
46.
Zhang HF, Zhang Y, Chen WD. Observation effect of leflunomide combined with glucocorticoids in comparison with cyclophosphamide glucocorticoid therapy on IgA nephropathy. Taishan Med Coll 2013;6:434-6.  Back to cited text no. 46
    
47.
Lv LP. Clinical observation of leflunomide combined with glucocorticoids in comparison with cyclophosphamide glucocorticoid therapy on lgA nephropathy. Chinese Journal of Practical Medicine 2015;14:97-8.  Back to cited text no. 47
    
48.
Chen XM, Chen P, Cai G, Wu J, Cui Y, Zhang Y, et al. A randomized control trial of mycophenolate mofeil treatment in severe IgA nephropathy. Natl Med J China 2002;82:796-801.  Back to cited text no. 48
    
49.
Tang SC, Tang AW, Wong SS, Leung JC, Ho YW, Lai KN. Long-term study of mycophenolate mofetil treatment in IgA nephropathy. Kidney Int 2010;77:543-9.  Back to cited text no. 49
    
50.
Chen XS, Zhang L. Clinic effect of mycophenolate mofetil combined valsartan on IgA nephropathy. Guide of China Medicine 2010;20:53-4.  Back to cited text no. 50
    
51.
Huang Z, Xiao J, Zhao ZZ. Observation of curativeefect of 38 cases with focalhy perplasia hardening of IgA nephropathy. He Nan Med Res 2012;4:437-9.  Back to cited text no. 51
    
52.
Wang WM, Jia XY, Pan XX, Shen PY, Liu J, Xu LL, et al. Clinical study on treatment of IgA nephropathy with renal insufficiency by corticosteroid, corticosteroid combined with cyclophosphamide and corticosteroid combined with mycophenolate mofetil. Journal of Shanghai Jiaotong University (Medical Science) 2013;2:162-7.  Back to cited text no. 52
    
53.
Hou JH, Le WB, Chen N, Wang WM, Liu ZS, Liu D, et al. Mycophenolate mofetil combined with prednisone versus full-dose prednisone in IgA nephropathy with active proliferative lesions: A randomized controlled trial. Am J Kidney Dis 2017;69:788-95.  Back to cited text no. 53
    
54.
Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, et al. Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study. Kidney Int 2014;65:1842-9.  Back to cited text no. 54
    
55.
Frisch G, Lin I, Rosenstock J, Markowitz G, D'Agati V, Radhakrishnan J, et al. Mycophenoate mofetil (MMF) VS placebo in patients with moderately advanced IgA nephropathy: A double-blind randomized controlled trial. Nephrol Dial Transplant 2015;20:2139-45.  Back to cited text no. 55
    
56.
Hogg RJ, Bay RC, Jenneette JC, Sibley R, Kumar S, Fervenza FC, et al. Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy. Am J Kidney Dis 2015;66:783-91.  Back to cited text no. 56
    
57.
Liu XW, Xu GS, Wang HM, Liu HB, Bai SR, Suan SR, et al. Mycophenolate mofetil therapy versus cyclophosphamide treatment in patients with severs IgA nephropathy. Medical Journal of National Defending Forces in Southwest China 2007;17:289-91.  Back to cited text no. 57
    
58.
Su QT. Mycophenolate mofetil therapy versus cyclophosphamide treatment in patients with sever IgA nephropathy. Chinese Journal of Ethnomedicine Ethnopharmaey 2009;18:101-3.  Back to cited text no. 58
    
59.
Wang W, Bi YB, He X, Qu LJ, Gao F, Xing J, et al. Comparison of clinical efficacy between prednisone combined with Mycophenolate mofetil or cyclophosphamide in patients with severs IgA nephropathy. Medical Journal of the Chinese People's Armed Police Forces 2013;24:792-795.  Back to cited text no. 59
    
60.
Liu XW, De DW, Su S, Xu G, Liu H, He L, et al. Treatment of severe IgA nephropathy: Mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone. Int J Clin Pharmacol Ther 2014;52:95-102.  Back to cited text no. 60
    
61.
Wang WJ, Shi J, Zhang T, Chen Q. The effect of prednison combined with CTX on the efficacy and renal function parameters in patients with IgA nephropathy. Laboratory Medicine and Clinic 2016;13:3043-5.  Back to cited text no. 61
    
62.
Song YY. Effects of tacrolimus (FK506) combined with low-dose glucocorticoid in the treatment of IgA nephropathy. Jilin University. 2010.  Back to cited text no. 62
    
63.
Zhang JX, Qian JZ. Clinical efficacy of tacrolimus combined with small does of hormone therapy on IgA nephropathy. Journal of Jiangsu University (Medicine Edition) 2013;23:263-7.  Back to cited text no. 63
    
64.
Shen PY, Jia XY, Wang ZH, Li Y, Pan X, Wang W, et al. The treatment of tacrolimus in primary IgA nephropathy with mild or moderate renal injury: A randomized controlled study. Chin J Nephrol 2014;30:885-90.  Back to cited text no. 64
    
65.
Wu GY, Chen XB, Jiang XL. Clinical study of tacrolimus combined with small dose of prednisolone in treatment of IgA nephropathy. Chin J Prim Med Pharm 2015;23:3619-22.  Back to cited text no. 65
    
66.
Hong M, Zhang DW, Mei YM, Wang XC, Wang SX, Ding N, et al. Tacrolimus combined with low-dose glucocorticoid clinical effect on patients with northern IgA Nephropathy. Clinical Journal of Medical Officer 2016;44:253-8.  Back to cited text no. 66
    
67.
Bao HM, Guo WG, Ren Z, Chen XM, Wang JH, Xin L. Curative effect observation of tacrolimus combined with glucocorticoid in the treatment of primary IgA nephropathy with mild to moderate renal injury. Medical Recapitulate 2016;22:2884-7.  Back to cited text no. 67
    
68.
Sun QC, Zhao HW, Li LN, Shen BB, Liu H. Clinical efficacy of low-dose tacrolimus combined with glucocorticoid on IgA nephropathy with moderate proteinuria: A report of 64 cases. J Third Military Med Univ 2017;39:481-6.  Back to cited text no. 68
    
69.
Fukuda M, Hotta O, Mizuno M, Ogiyama Y, Ohte N. Immunosuppressive therapy for active IgA nephropathy is effective and safe, even in “elderly” patients. Clin Exp Nephrol 2016;20:1-3.  Back to cited text no. 69
    
70.
Shen XH, Liang SS, Chen HM, Le WB, Jiang S, Zeng CH, et al. Reversal of active glomerular lesions after immunosuppressive therapy in patients with IgA nephropathy: A repeat-biopsy based observation. J Nephrol 2015;8:441-9.  Back to cited text no. 70
    
71.
Beckwith H, Medjeralthomas N, Galliford J, Griffith M, Levy J, Lightstone L, et al. Mycophenolate mofetil therapy in immunoglobulin A nephropathy: Histological changes after treatment. Nephrol Dial Transplant 2017;32:i123-8.  Back to cited text no. 71
    
72.
Hackl A, Ehren R, Weber LT. Effect of mycophenolic acid in experimental, nontransplant glomerular diseases: New mechanisms beyond immune cells. Pediatr Nephrol 2017;32:1315-22.  Back to cited text no. 72
    
73.
Van der Woude FJ. Mycophenolate mofetil (RS 61443): Nothing new under the sun or an important break-through in the field of transplantation? Nephrol Dial Transplant 1995;10:1112-5.  Back to cited text no. 73
    


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