Immunosuppressive agents for treating IgA nephropathy

Patrizia Natale; Suetonia C Palmer; Marinella Ruospo; Valeria M Saglimbene; Jonathan C Craig; Mariacristina Vecchio; Joshua A Samuels; Donald A Molony; Francesco Paolo Schena; Giovanni FM Strippoli

doi:10.1002/14651858.CD003965.pub3

. 2020 Mar 12;2020(3):CD003965. doi: 10.1002/14651858.CD003965.pub3

Immunosuppressive agents for treating IgA nephropathy

Patrizia Natale ^1,², Suetonia C Palmer ³, Marinella Ruospo ^1,², Valeria M Saglimbene ^1,², Jonathan C Craig ^4,⁵, Mariacristina Vecchio ⁶, Joshua A Samuels ⁷, Donald A Molony ⁸, Francesco Paolo Schena ¹, Giovanni FM Strippoli ^1,^2,^4,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7066485 PMID: 32162319

Abstract

Background

IgA nephropathy is the most common glomerulonephritis world‐wide. IgA nephropathy causes end‐stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015.

Objectives

To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

We included randomised controlled trials (RCTs) and quasi‐RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non‐immunosuppressive agents.

Data collection and analysis

Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta‐analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology.

Main results

Fifty‐eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains.

In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD ‐0.58 g/24 h, 95% CI ‐0.84 to ‐0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events.

Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported.

Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported.

Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported.

Mizoribine administered with renin‐angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported.

Leflunomide followed by a tapering course with oral prednisone compared to prednisone had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, and infection. Death and malignancy were not reported.

Effects of other immunosuppressive regimens (including steroid plus non‐immunosuppressive agents or mTOR inhibitors) were inconclusive primarily due to insufficient data from the individual studies in low or very low certainty evidence. The effects of treatments on death, malignancy, reduction in GFR at least of 25% and adverse events were very uncertain. Subgroup analyses to determine the impact of specific patient characteristics such as ethnicity or disease severity on treatment effectiveness were not possible.

Authors' conclusions

In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low‐quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment‐related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.

Plain language summary

Immunosuppressive agents for treating IgA nephropathy

What is the issue?  IgA nephropathy is a common kidney disease that often leads to decreased kidney function and may result ultimately in kidney failure for one‐third of affected people. The cause of IgA nephropathy is not known, although most people with the disease have abnormalities in their immune system.

What did we do?  We searched for all the research trials that assessed the effect of immunosuppressive therapy in people with IgA nephropathy in September 2019. We measured the certainty we could have about the treatments using a system called "GRADE".

What did we find?  We found 58 studies involving 3933 adults and children who were treated with immunosuppressive therapy. Patients in the studies were given either steroids or other forms of therapy to reduce the actions of their immune system. The treatment they got was decided by random chance. Steroid therapy taken for 2 to 4 months appeared to slow damage to the kidney and probably prevents patients from developing kidney failure. It is really uncertain whether steroids cause side effects such as serious infection. One study was stopped early because patients who received steroid therapy had more infections than those patients who were given placebo. Other medications like cyclophosphamide, azathioprine, and mycophenolate mofetil did not clearly protect kidney function in people with IgA nephropathy.

Conclusions

Steroid therapy may prevent kidney failure in IgA nephropathy but the risks of serious infections are uncertain with treatment.

Summary of findings

Background

Description of the condition

IgA nephropathy was first described in 1968 by Dr J. Berger. Characterised by prominent mesangial IgA deposits seen diffusely on immunofluorescence microscopy, the condition was initially thought to be a rare and benign cause of recurrent haematuria (Berger 1968). It has since become apparent, however, that IgA nephropathy is neither rare nor benign. Although biopsy practices differ from region to region, thus affecting the frequency of diagnosis of IgA nephropathy, it has been demonstrated that IgA nephropathy is the most common glomerular disease world‐wide (D'Amico 1987; Han 2010) with a variable prevalence ranging from 5% to more than 40% (Schena 2009).

The natural history of IgA nephropathy is now known to be highly heterogeneous and far from benign in many patients. While up to 50% of patients experience lasting remission (Kim 2016; Nolin 1999), 40% can develop end‐stage kidney disease (ESKD) within 20 years (Manno 2007), while another 30% to 40% experience decreased kidney function (Inagaki 2017; Rekola 1991). Overall, as many as 15% to 50% of those affected develop chronic kidney disease (CKD) and eventually ESKD (Rostoker 1995; Schena 2001). Studies have demonstrated that risk factors associated with disease progression include evidence of proteinuria, especially in people with proteinuria < 1 g/day (Reich 2007), hypertension (Liu 2019) or elevated serum creatinine (SCr) at the time of kidney biopsy, microhematuria at diagnosis (Gallo 1988; Manno 2007; Neelakantappa 1988), and specific histological lesions (as reported in the Oxford classification) (Cattran 2009; Haas 2017; Trimarchi 2017). These prognostic data may help stratify those patients at highest need for effective therapy.

Evidence suggests that IgA nephropathy is a consequence of abnormal glycosylation of O‐linked glycans in the hinge region of IgA1, resulting in increased circulation of galactose‐deficient IgA1 (Gd‐IgA1) (Gale 2017; Mestecky 1993). Most patients have some abnormalities of the immune system some time in their disease course, including increased circulating IgA or some other humoral or cellular abnormality. It has been shown that the IgA molecules deposited in the glomerular mesangium have the same abnormalities of glycosylation (Hiki 2001). Altered IgA glycosylation may enhance mesangial deposition due to the formation of pathogenic immune complexes or by promoting IgA molecular interactions with kidney matrix proteins and/or mesangial cell immune receptors.

Complement system activation occurs in IgA nephropathy through the alternative and lectin pathways, with complement components identified in pathogenic mesangial deposits (Maillard 2015), Evidence for complement activity in the progression of IgA nephropathy glomerular injury has led to the development of short interfering RNA molecules (siRNA) against complement component 5 (C5) which is undergoing evaluation in a phase 2 randomised controlled trial (RCT) (NCT03841448).

Description of the intervention

Despite better understanding of the pathogenic mechanisms causing IgA nephropathy, there is no established disease‐targeted treatment for IgA nephropathy and various treatments have been applied, including corticosteroid, azathioprine (AZA), calcineurin inhibitors (CNIs), cyclophosphamide (CPA), mycophenolate mofetil (MMF), rituximab and leflunomide (Hou 2017; Lafayette 2017; Locatelli 1999; Pozzi 2010; Song 2017).

IgA nephropathy has been identified as having an inflammatory basis leading to the biological rationale of corticosteroid therapy (Coppo 2018). Over the last decades, some studies have reported that intravenous steroid pulse therapy in combination with oral prednisolone are effective for reducing proteinuria and preventing ESKD, as well as increasing 10‐year survival (Pozzi 1999). Evidence from observational studies (Tesar 2015) and RCTs (TESTING 2017) showed potential benefits of corticosteroid treatment in patients with proteinuric IgA nephropathy, although severe infectious complications and a higher mortality risk has suggested the need to evaluate intervention strategies that have lower toxicity.

Tonsillectomy combined with steroid pulse therapy has been shown to induce had a significant impact on clinical remission of IgA proteinuria and may be beneficial for long‐term kidney survival (Hotta 2001). In Asian countries, tonsillectomy is performed in at least 50% of adults with IgA nephropathy, however genetic variation may impact on IgA susceptibility and therapeutic response to this intervention strategy (Hirano 2019). By contrast, some studies have shown no therapeutic effect of corticosteroid (Lai 1986) and tonsillectomy (Piccoli 2010) in patients with IgA nephropathy leading to therapeutic uncertainty.

The recent focus on the role of gut–kidney axis in IgA nephropathy has led to development of selective corticosteroid formulations targeting the intestinal mucosal immune system, aiming to reduce proteinuria and stabilise kidney function with fewer systemic adverse events from steroid therapy (NEFIGAN 2017).

Patients may not always respond to corticosteroid therapy leading to consideration of additive immunosuppressive therapies to obtain a synergistic effect. Although IgA nephropathy is likely an autoimmune kidney disease, there is uncertainty about whether some immunosuppressive agents such as AZA or CPA suppress disease activity, reduce proteinuria or protect kidney function particularly in the absence of rapidly progressive glomerulonephritis (Locatelli 1999; Walker 1990a). The supportive versus immunosuppressive therapy for the treatment of progressive IgA nephropathy (STOP‐IgAN 2008) RCT showed that combined corticosteroid and immunosuppressive therapy may be superior to supportive care alone.

CNIs possess potent immunosuppressive properties, suppressing the activation and proliferation of T cells to inhibit synthesis of interleukin (IL)‐2. This suppresses secondary synthesis of various cytokines, including IL‐4 and tumour necrosis factor‐alpha. Despite these immunomodulating effects, there are limited data for protection of kidney function and evidence of increased side effects with CNIs (Song 2017).

MMF selectively inhibits the proliferation of T and B lymphocytes, antibody production, generation of cytotoxic T cells and the recruitment of leukocytes to sites of inflammation. However, experimental evidence has not clearly shown that the anti‐inflammatory properties of MMF, by attenuating glomerular and interstitial injury, are beneficial in the treatment of progressive IgA nephropathies with an acceptable safety profile (Maes 2004).

Few RCTs have evaluated the efficacy of leflunomide in the treatment of IgA nephropathy to demonstrate reduction in proteinuria and protection of kidney function (Cheng 2015). Leflunomide, generally evaluated in China, has very limited efficacy data (Lou 2006).

There has been limited stratification by risk of ESKD or disease severity in studies evaluating IgA nephropathy management. Substantial disease heterogeneity suggests a validated tool for IgA nephropathy could support accurate prediction of disease progression and enrich trial populations with patients at highest risk of ESKD (Barbour 2019). Although clinical evidence suggests that treatment of IgA nephropathy with either single and combined treatments regimen can lead to partial or complete remission and prevent loss of kidney function, some patients still experience progressive kidney injury (Moriyama 2019). The protective role of immunosuppressive therapy has been uncertain in part due to the small sample sizes and short duration therapy and follow‐up in available studies. In addition, global heterogeneity in disease activity and susceptibility based on ethnicity may impact on interpretation of treatment efficacy in different ethnicity groups and international regions (Kiryluk 2012). As a consequence of fewer data and heterogeneous disease activity in existing studies, the longer term effects of immunosuppression have been uncertain.

How the intervention might work

IgA nephropathy often progresses very slowly, taking decades to reach the clinical outcomes usually studied in clinical studies (death and need for dialysis or kidney transplantation). It has thus been difficult to establish the most effective treatment regimen for IgA nephropathy. Reviews have examined the evidence for treatment of both adults (Nolin 1999) and children (Wyatt 2001) with IgA nephropathy to find optimal regimens. These analyses included studies of varying methodological quality, and are mostly case series and other forms of non‐randomised evaluation. These data have resulted in conflicting information regarding the optimal therapy. The most commonly used regimens include immunosuppressive agents such as glucocorticoids (steroids), cyclosporin A (CSA), or CPA. Additionally, non‐immunosuppressive medications including fish oils, anticoagulants, antihypertensive agents and surgical tonsillectomy with and without immunosuppression have been tested in a variety of studies including RCTs.

Why it is important to do this review

Given the burden of disease and the known risks of progression, as well as the lack of an accepted effective therapy, a systematic review of these treatments was necessary to aid healthcare providers in managing this condition. The present review focuses on the benefits and harms of immunosuppressive treatment for IgA nephropathy. The initial review was published in 2003 (Samuels 2003b; Samuels 2004) and was updated in 2015 (Vecchio 2015).

A separate review summarises the benefits and harms of non‐immunosuppressive treatments for IgA nephropathy (Reid 2011).

Objectives

To determine the benefits and harms of immunosuppression for the treatment of IgA nephropathy.

Methods

Criteria for considering studies for this review

Types of studies

RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that compared immunosuppressive therapy (corticosteroids, cytotoxic agents, MMF, leflunomide, or other) with other immunosuppressive agents, non‐immunosuppressive treatment (including antihypertensive agents and anticoagulants), or placebo or no treatment/standard care for the treatment of IgA nephropathy were included.

Types of participants

Adult and children with biopsy‐proven IgA nephropathy.

Types of interventions

Immunosuppressive agent versus placebo, no treatment/standard care, or other non‐immunosuppressive agent (including renin‐angiotensin system (RAS) inhibitors)
Head to head comparisons between immunosuppressive agents.

Types of outcome measures

Primary outcomes

ESKD requiring kidney replacement therapy (KRT) (dialysis or kidney transplantation)
Complete remission: defined by a reduction in urinary protein excretion to less than 1 g/24 hours in three consecutive daily samples or as defined by the investigators
Doubling of SCr
SCr (µmol/L)
Estimated or measured glomerular filtration rate (GFR) (either creatinine clearance (CrCl) (mL/min) or Cockcroft clearance (mL/min/1.73 m²)
Urinary protein excretion (g/24 hours)

Secondary outcomes

Death
Infection
Malignancy

Where possible, time to reach the above end‐points in each treatment arm was included in the analysis.

Adverse effects

Dropout rate due to treatment‐related adverse events
Bone density, fracture or shorter stature

Search methods for identification of studies

Electronic searches

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Searches of kidney and transplant journals, and the proceedings and abstracts from major kidney and transplant conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.
Grey literature sources (e.g. abstracts, dissertations and theses), in addition to those already included in the Cochrane Kidney and Transplant Register of Studies, were searched.

Data collection and analysis

The initial review was undertaken by five authors (JAS, GFMS, JCC, FPS, DAM) and was updated by 10 authors (PN, SCP, MR, VS, JCC, MV, JAS, DAM, FPS, GFMS).

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts were screened independently by at least two authors, who discarded studies that were not applicable; however, studies and reviews that may have included relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, where necessary the full text, of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by at least two authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports be grouped together and the publication with the most complete data was used in the analyses. When relevant outcomes were only published in earlier versions these data were used. Any discrepancies between published versions were to highlighted.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2011) (seeAppendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (mortality, infection, ESKD, doubling of SCr, malignancy, reduction in GFR at least 25 or 50%, complete remission, adverse events) results were expressed as relative risk (RR) with 95% confidence intervals (CI) for individual studies. When continuous scales of measurement were used, we assessed the effects of treatment (SCr, CrCl, annual GFR loss and urinary protein excretion), using the mean difference (MD), or the standardised mean difference (SMD) if different scales had been used. Adverse events were summarised descriptively. As measures of proteinuria and albuminuria were reported using various measures, including relative to urinary creatinine, we have harmonised all endpoints to a single measure of milligrams per day or excretion. We followed the methods reported by Lambers Heerspink 2015 to convert the albumin excretion rate per day to protein excretion rate by dividing the albumin excretion by 0.6, recognising that a total daily protein excretion of 500 mg/day is approximately equal to 300 mg/day of albumin.

Dealing with missing data

Any further information required from the original author was requested by written correspondence (e.g. emailing or writing to corresponding author) and any relevant information obtained in this manner was included in the review.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows:

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

It was planned that if sufficient RCTs were identified, an attempt would be made to assess for publication bias using a funnel plot (Egger 1997). However, insufficient data precluded subgroup analyses in this review update.

Data synthesis

Treatment effects were summarised using a random effects model. For each analysis, the fixed effects model was also evaluated to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was planned to explore how possible sources of heterogeneity (paediatric versus adult population, stage of renal biopsy, race of participants) might have influenced the treatment effects observed. However, due to the small number of studies, subgroup analyses to determine the impact of patient characteristics on treatment effectiveness were not possible.

Post hoc subgroup analysis

We performed a post hoc subgroup analysis to assess the effect of the background of treatments with and without RAS blockade and blood pressure (BP) control (ACE inhibitor and/or ARB) on risks of ESKD.

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We presented the following outcomes in the 'Summary of findings' tables.

We presented the following outcomes in the 'Summary of findings' table:

ESKD
Complete remission
≥ 50% GFR loss
Annual GFR loss (mL/min/1.73 m²)
Death (any cause)
Infection
Malignancy

Results

Description of studies

Results of the search

Search results are shown in Figure 1. For this 2020 review update, we identified 69 new reports. There were 36 new studies (56 reports) and 13 new reports of 10 existing studies. Seventeen new studies (38 reports) were eligible (BRIGHT‐SC 2016; CAST‐IgA 2015; Cheung 2018; Hirai 2017; Hou 2017; Koitabashi 1996; Lee 2003; Masutani 2016; Min 2017; NEFIGAN 2017; Shen 2013; Shi 2012a; Shima 2018; STOP‐IgAN 2008; TESTING 2017; Wu 2016; Yamauchi 2001) and three studies (three reports) were excluded (GloMY 2010; Imai 2006; Yonemura 2000b).

There are 13 ongoing studies (AIGA 2016; ARTEMIS‐IgAN 2018; ChiCTR1800014442; MAIN 2013; NCT00657059; NCT02808429; NCT03468972; NEFIGARD 2018; PIRAT 2015; SIGN 2014; TIGER 2017; TOPplus‐IgAN 2013; UMIN000032031) that have not yet been completed according to details held within the www.ClinicalTrials.gov registry, www.chictr.org.cn and https://upload.umin.ac.jp/; and three studies are awaiting classification while we try to determine if they meet our inclusion criteria (NCT00301600; NCT02160132; NCT02571842). These 16 studies will be assessed in a future update of this review.

In addition, four previous ongoing studies (2nd NA IgAN 2004; Hou 2017; Lafayette 2017; STOP‐IgAN 2008) and eight studies awaiting assessment (Chen 2002; Cruzado 2011; Kawamura 2014; Kim 2013b; Liu 2010a; Liu 2014; Stangou 2011; Xie 2011) have been reclassified as included. One ongoing study (Dal Canton 2005) and three studies awaiting classification have been reclassified as excluded (Chen 2009b; Czock 2007; Shen 2009).

For this 2020 update there are 58 included studies, 13 ongoing studies, 3 studies awaiting assessment and 8 excluded studies. Non‐RCTs have been removed from this update.

Included studies

The characteristics of the participants and the interventions in included studies are detailed in the Characteristics of included studies. Overall, 58 studies (151 publications) enrolling a total of 3933 patients, were included in this review update (2nd NA IgAN 2004; Ballardie 2002; BRIGHT‐SC 2016; Cao 2008; CAST‐IgA 2015; Chen 2002; Cheung 2018; Cruzado 2011; Frisch 2005; Harmankaya 2002; Hirai 2017; Horita 2007; Hou 2017; Julian 1993; Kanno 2003; Katafuchi 2003; Kawamura 2014; Kim 2013b; Kobayashi 1996; Koike 2008; Koitabashi 1996; Lafayette 2017; Lai 1986; Lai 1987; Lee 2003; Liu 2010a; Liu 2014; Locatelli 1999; Lou 2006; Lv 2009; Maes 2004; Manno 2001; Masutani 2016; Min 2017; NA IgAN 1995; NEFIGAN 2017; Ni 2005; Nuzzi 2009; Pozzi 1999; Segarra 2006; Shen 2013; Shi 2012a; Shima 2018; Shoji 2000; Stangou 2011; STOP‐IgAN 2008; Takeda 1999; Tang 2005; TESTING 2017; Walker 1990a; Welch 1992; Woo 1987; Wu 2016; Xie 2011; Yamauchi 2001; Yoshikawa 1999; Yoshikawa 2006; Zhang 2004). Ten authors were contacted for clarifications relating to their publications and to request additional unpublished information. Four authors replied to our request.

Six studies included paediatric participants (Kobayashi 1996; Nuzzi 2009; Shima 2018; Welch 1992; Yoshikawa 1999; Yoshikawa 2006). Twenty‐six studies included people with daily protein excretion > 1 g/24 hours (Cao 2008; Chen 2002; Cruzado 2011; Frisch 2005; Horita 2007; Hou 2017; Kawamura 2014; Lee 2003; Kobayashi 1996; Lai 1987; Liu 2014; Locatelli 1999; Lou 2006; Lv 2009; Maes 2004; Manno 2001; Min 2017; Ni 2005; Pozzi 1999; Segarra 2006; Shen 2013; Shi 2012a; Stangou 2011; Tang 2005; TESTING 2017; Walker 1990a). Thirteen studies (BRIGHT‐SC 2016; Chen 2002; Cheung 2018; Kawamura 2014; Koitabashi 1996; Lafayette 2017; Nuzzi 2009; Segarra 2006; Shi 2012a; Shima 2018; Takeda 1999; Welch 1992; Yamauchi 2001) did not report data in an extractable format that could be included in our meta‐analysis.

We identified five study of head‐to‐head comparisons between different immunosuppressive agents (Chen 2002; Hou 2017; Liu 2010a; Shen 2013; Wu 2016) and there were no studies that compared different doses of the same immunosuppressive agents.

See Characteristics of included studies.

Excluded studies

We excluded eight studies (nine reports) as they did not include all participants with IgA nephropathy (Imai 2006; Sulimani 2001; Yonemura 2000b), did not evaluate a immunosuppressive agent intervention (Chen 2009b; Czock 2007; Shen 2009), or did not complete the participant recruitment (Dal Canton 2005; GloMY 2010). See Characteristics of excluded studies.

Risk of bias in included studies

The risks of bias in the included studies are summarised in Figure 2. Risks of bias in individual studies are shown in Figure 3 and described in the Characteristics of included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation was considered at low risk of bias in 15 studies (2nd NA IgAN 2004; Hirai 2017; Julian 1993; Kawamura 2014; Kim 2013b; Locatelli 1999; Lv 2009; Manno 2001; NEFIGAN 2017; Pozzi 1999; Shoji 2000; Stangou 2011; TESTING 2017; Welch 1992; Wu 2016), at high risk in two studies (Kobayashi 1996; Lai 1987), and unclear in the remaining 41 studies.

Allocation concealment was adjudicated as low risk of bias in two studies (Manno 2001; TESTING 2017), at high risk in four studies (Kawamura 2014; Kobayashi 1996; Lai 1986; Lai 1987); and unclear in the remaining 52 studies.

Blinding

Nine studies (2nd NA IgAN 2004; BRIGHT‐SC 2016; Cheung 2018; Frisch 2005; Kim 2013b; NEFIGAN 2017; TESTING 2017; Welch 1992; Wu 2016) were blinded and considered to be at low risk of bias and one study (Lee 2003) was assessed as unclear risk of performance bias. The remaining 48 studies were not blinded and were considered at high risk of performance bias.

Outcome assessment was considered to be at low risk of detection bias in 25 studies (Ballardie 2002; BRIGHT‐SC 2016; Cao 2008; CAST‐IgA 2015; Horita 2007; Hou 2017; Kanno 2003; Katafuchi 2003; Kobayashi 1996; Koike 2008; Koitabashi 1996; Lai 1986; NEFIGAN 2017; Nuzzi 2009; Shoji 2000; Takeda 1999; TESTING 2017; Walker 1990a; Welch 1992; Woo 1987; Wu 2016; Xie 2011; Yamauchi 2001; Yoshikawa 1999; Yoshikawa 2006), unclear in one study (Lee 2003), and high risk the remaining 32 studies.

Incomplete outcome data

Eighteen studies were judged to be a low risk of attrition bias (Ballardie 2002; Cruzado 2011; Frisch 2005; Horita 2007; Hou 2017; Kim 2013b; Koike 2008; Lai 1986; Liu 2010a; Lv 2009; Manno 2001; Masutani 2016; Shima 2018; STOP‐IgAN 2008; Tang 2005; Walker 1990a; Welch 1992; Yoshikawa 2006), 25 studies were at high risk of attrition bias (2nd NA IgAN 2004; BRIGHT‐SC 2016; Harmankaya 2002; Hirai 2017; Julian 1993; Kanno 2003; Katafuchi 2003; Kobayashi 1996; Lafayette 2017; Lai 1987; Liu 2014; Locatelli 1999; Lou 2006; Maes 2004; Min 2017; NA IgAN 1995; NEFIGAN 2017; Ni 2005; Pozzi 1999; Segarra 2006; Shoji 2000; TESTING 2017; Wu 2016; Xie 2011; Yoshikawa 1999), and the remaining 15 studies were unclear.

Selective reporting

Thirteen studies were judged to be at low risk of reporting bias (Cruzado 2011; Frisch 2005; Locatelli 1999; Lv 2009; Maes 2004; Manno 2001; NEFIGAN 2017; Pozzi 1999; STOP‐IgAN 2008; Tang 2005; TESTING 2017; Walker 1990a; Wu 2016), one study was unclear (Lee 2003), and 44 were at high risk of reporting bias.

Other potential sources of bias

We adjudicated 22 studies as low risk of bias from other potential sources (Harmankaya 2002; Hirai 2017; Horita 2007; Hou 2017; Kanno 2003; Katafuchi 2003; Kawamura 2014; Kim 2013b; Liu 2010a; Liu 2014; Locatelli 1999; Lv 2009; Maes 2004; Min 2017; Shima 2018; Shoji 2000; STOP‐IgAN 2008; Tang 2005; Walker 1990a; Wu 2016; Xie 2011; Yoshikawa 2006) considering balance of participant characteristics and co‐interventions, governmental or academic sources of funding and balanced timing of outcome assessment for all treatment groups. Eighteen studies (2nd NA IgAN 2004; Cruzado 2011; Frisch 2005; Kobayashi 1996; Koike 2008; Lafayette 2017; Lai 1986; Lai 1987; Lou 2006; Masutani 2016; NA IgAN 1995; NEFIGAN 2017; Pozzi 1999; Segarra 2006; Stangou 2011; TESTING 2017; Woo 1987; Yoshikawa 1999) was assessed as high risk of bias. Risk of bias was unclear in the remaining 18 studies.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6

Summary of findings for the main comparison. Systemic corticosteroid versus no corticosteroid regimen for IgA nephropathy.

Systemic corticosteroid versus no corticosteroid regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Setting: Australia, China, Europe, Japan, USA Intervention: corticosteroid regimen (includes steroids alone or with RAS inhibitors) Comparison: no corticosteroid regimen
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk with no steroids	Risk with steroids	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease Follow‐up: 2 to 10 years	141 per 1000	55 per 1000 (32 to 92)	RR 0.39 (0.23 to 0.65)	741 (8)	⊕⊕⊕⊝  moderate ¹
Complete remission Follow‐up: 2 to 5 years	364 per 1000	641 per 1000  (375 to 1000)	RR 1.76 (1.03 to 3.01)	305 (4)	⊕⊕⊝⊝  low ^1,3
GFR loss ≥ 50% Follow‐up: 2 to 2.1 years	96 per 1000	54 per 1000 (24 to 119)	RR 0.56 (0.25 to 1.24)	326 (2)	⊕⊕⊝⊝  low ^1,2
Annual GFR loss (mL/min/1.73 m²) Follow‐up: 2.1 to 5 years	The mean annual GFR loss ranged across control groups from 6.17 to 6.95 mL/min/1.73 m²	The mean annual GFR loss in the intervention group was ‐5.40 mL/min/1.73 m² less than the control group (95% CI ‐8.55 less to ‐2.25 less)	‐‐	359 (2)	⊕⊕⊕⊝  moderate ¹
Death (any cause) Median follow‐up: 2.1 years	8 per 1000	15 per 1000 (1 to 162)	RR 1.85 (0.17 to 20.19)	262 (1)	⊕⊝⊝⊝  very low ^1,4
Infection Median follow‐up: 2.1 years	No events	11/136**	RR 21.32 (1.27, 358.10)	262 (1)	⊕⊝⊝⊝  very low ^1,2,3
Malignancy Follow‐up: 6 years	23 per 1000	23 per 1000 (1 to 356)	RR 1.00 (0.06 to 15.48)	86 (1)	⊕⊝⊝⊝  very low ^1,2,4
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio ** Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Cytotoxic regimen versus no cytotoxic regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Settings: Australia, China, Europe, Japan Intervention: cytotoxic therapy (including combinations of cyclophosphamide or azathioprine with steroid therapy) Comparison: no cytotoxic therapy
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk with no cytotoxic therapy	Risk with cytotoxic therapy	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease Follow‐up: 1 to 7 years	166 per 1000	105 per 1000 (55 to 199)	RR 0.63 (0.33 to 1.20)	463 (7)	⊕⊕⊝⊝  low ^1,3
Complete remission Follow‐up: 0.5 to 5 years	337 per 1000	495 per 1000 (317 to 775)	RR 1.47 (0.94 to 2.30)	381 (5)	⊕⊝⊝⊝  very low ^1,3,4
GFR loss ≥ 50%	No data observations	Not estimable	No studies	No studies	Not estimable
Annual GFR loss (mL/min/1.73 m²) Follow‐up: 3 years	The mean GFR loss was 0.01 mL/min/1.73 m² in the control group	The mean GFR loss in the intervention group was 0.01 mL/min/1.73 m² lower than the control group (95% CI ‐0.03 to 0.01)	‐‐	162 (1)	⊕⊕⊝⊝  low ^1,3
Death (any cause) Follow‐up: 3 years	13 per 1000	13 per 1000 (1 to 199)	RR 0.98 (0.06 to 15.33)	162 (1)	⊕⊝⊝⊝  very low ^1,2
Infection Follow‐up: 1 to 7 years	22 per 1000	37 per 1000 (10 to 149)	RR 1.70 (0.43 to. 6.76)	268 (4)	⊕⊝⊝⊝  very low ^1,2
Malignancy Follow‐up: 3 years	No events	2/82**	RR 4.88 (0.24 to 100.08)	162 (1)	⊕⊝⊝⊝  very low ^1,2
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio ** Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

MMF regimen versus no MMF regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Settings: Australia, China, Europe Intervention: MMF regimen (includes MMF alone, or in combination with RAS inhibitors or steroids) Comparison: mo MMF regimen
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk without MMF	Risk with MMF	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease Follow‐up: 1 to 3 years	96 per 1000	70 per 1000 (15 to 310)	RR 0.73 (0.16 to 3.23)	280 (4)	⊕⊝⊝⊝  very low ^1,2,3
Complete remission Follow‐up: 1 to 2 years	267 per 1000	280 per 1000 (195 to 406)	RR 1.05 (0.73 to 1.52)	271 (4)	⊕⊝⊝⊝  very low ^1,2
GFR loss ≥ 50% Follow‐up: 2 years	133 per 1000	294 per 1000 (67 to 1000)	RR 2.21 (0.50 to 9.74)	32 (1)	⊕⊝⊝⊝  very low ^1,2
Annual GFR loss (mL/min/1.73 m²) Follow‐up: 1 year	The mean GFR loss was 10.6 mL/min/1.73 m² in the control group	The mean GFR loss in the intervention group was 2.00 mL/min/1.73 m² lower than the control group (95% CI ‐25.15 to 29.15)	‐‐	28 (1)	⊕⊝⊝⊝  very low ^1,2
Death (any cause)	No data observations	Not estimable	No studies	No studies	Not estimable
Infection Follow‐up: 1 to 3 years	169 per 1000	230 per 1000 (147 to 358)	RR 1.36 (0.87 to 2.12)	301 (4)	⊕⊝⊝⊝  very low ^1,2
Malignancy Follow‐up: 1 to 3 years	50 per 1000	14 per 1000 (2 to 127)	RR 0.28 (0.03 to 2.54)	86 (2)	⊕⊝⊝⊝  very low ^1,2
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Calcineurin inhibitor regimen versus no calcineurin inhibitor regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Settings: China Intervention: calcineurin inhibitor regimen (includes calcineurin inhibitor alone or in combination with steroids) Comparison: no calcineurin inhibitor regimen
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk without calcineurin inhibitor	Risk with calcineurin inhibitor	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease	No data observations	Not estimable	No studies	No studies	Not estimable
Complete remission Follow‐up: 0.5 to 1 year	541 per 1000	492 per 1000 (325 to 752)	RR 0.91 (0.60 to 1.39)	72 (2)	⊕⊝⊝⊝  very low ^1,2
GFR loss ≥ 50%	No data observations	Not estimable	No studies	No studies	Not estimable
Annual GFR loss (mL/min/ 1.73 m²)	No data observations	Not estimable	No studies	No studies	Not estimable
Death (any cause)	No data observations	Not estimable	No studies	No studies	Not estimable
Infection Follow‐up: 1 year	130 per 1000	40 per 1000 (4 to 356)	RR 0.31 (0.03 to 2.74)	48 (1)	⊕⊝⊝⊝  very low ^1,2
Malignancy Follow‐up: 1 year	40 per 1000	14 per 1000 (1 to 338)	RR 0.36 (0.02 to 8.45)	48 (1)	⊕⊝⊝⊝  very low ^1,2
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Mizoribine regimen compared with no mizoribine regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Settings: Japan Intervention: mizoribine regimen (includes mizoribine alone or with RAS inhibitors) Comparison: no mizoribine regimen
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk without mizoribine	Risk with mizoribine	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease Follow‐up: 3 years	48 per 1000	48 per 1000 (3 to 718)	RR 1.00 (0.07 to 14.95)	42 (1)	⊕⊝⊝⊝  very low ^1,2
Complete remission Follow‐up: 3 years	467 per 1000	887 per 1000 (495 to 1000)	RR 1.90 (1.06 to 3.43)	24 (1)	⊕⊝⊝⊝  very low ^1,2
GFR loss ≥ 50%	No data observations	Not estimable	No studies	No studies	Not estimable
Annual GFR loss (mL/min/1.73 m²)	No data observations	Not estimable	No studies	No studies	Not estimable
Death (any cause)	No data observations	Not estimable	No studies	No studies	Not estimable
Infection Follow‐up: 1 to 2.1 years	60 per 1000	91 per 1000 (8 to 969)	RR 1.52 (0.14 to 16.15)	104 (2)	⊕⊝⊝⊝  very low ^1,2,3
Malignancy Follow‐up: 3 years	No events	1/21**	RR 3.00 (0.13 to 69.70)	42 (1)	⊕⊝⊝⊝  very low ^1,2
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio. ** Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Leflunomide regimen compared with no leflunomide regimen for IgA nephropathy
Patient or population: adults and children who have IgA nephropathy proven on renal biopsy Settings: China Intervention: leflunomide regimen (includes leflunomide alone or with steroids or RAS inhibitor) Comparison: no leflunomide regimen
Outcomes	*Anticipated absolute benefits (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk without leflunomide	Risk with leflunomide	Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
End‐stage kidney disease Follow‐up: 7.3 years	111 per 1000	76 per 1000 (19 to 294)	RR 0.68 (0.17 to 2.65)	85 (1)	⊕⊝⊝⊝  very low ^1,2
Complete remission Follow‐up: 0.25 to 7.3 years	357 per 1000	386 per 1000 (286 to 521)	RR 1.08 (0.80 to 1.46)	282 (4)	⊕⊝⊝⊝  very low ^1,2
GFR loss ≥ 50%	No data observations	Not estimable	No studies	No studies	Not estimable
Annual GFR loss (mL/min/1.73 m²)	No data observations	Not estimable	No studies	No studies	Not estimable
Death (any cause)	No data observations	Not estimable	No studies	No studies	Not estimable
Infection Follow‐up: 0.5 to 7.3 years	56 per 1000	54 per 1000 (25 to 117)	RR 0.97 (0.45 to 2.09)	387 (3)	⊕⊝⊝⊝  very low ^1,2
Malignancy	No data observations	Not estimable	No studies	No studies	Not estimable
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Study ID	Intervention	Reported side effect	Number of events in treatment group (N)	Number of events in control group (N)
2nd NA IgAN 2004	MMF versus placebo	Malignant melanoma, multiple intra‐abdominal injuries	0+1 (13)	1+0 (15)
Ballardie 2002	Steroids + CPA versus no treatment	Pulmonary TB, overt diabetes, bone marrow toxicity, gastrointestinal toxicity	1+1+1+1 (19)	0+0+0+0 (19)
BRIGHT‐SC 2016	Carboxylic acids (Blisibimod) versus placebo	Not reported	Not reported	Not reported
Cao 2008	Steroids + leflunomide versus steroids	None reported	0 (18)	0 (18)
CAST‐IgA 2015	Steroid + prednisolone + tonsillectomy + ARB versus steroid + prednisolone	Not reported	Not reported	Not reported
Chen 2002	MMF versus prednisone	Diarrhoea, herpes zoster, nausea	% participants reported diarrhoea, herpes zoster, nausea (31)	Not reported
Cheung 2018	Belimumab versus placebo	Not reported	Not reported	Not reported
Cruzado 2011	Macrolide lactams (sirolimus) versus usual care	Fever, reversible hyperkalaemia, prostatic syndrome, unspecific acute gastritis, cholesterol increase, anaemia, oedema, mild facial rash	0+1+1+1+2+1+2+2 (14)	1+1+0+0+0+0+0+0 (9)
Frisch 2005	MMF versus placebo	Gastrointestinal effects, deep vein thrombosis	2+0 (17)	2+1 (15)
Harmankaya 2002	Steroids + AZA versus no treatment	Increased transaminase levels, minor cushingoid features, gastric pain	1+2+1 (21)	0 (22)
Hirai 2017	Mizoribine versus usual care	Hepatotoxicity, low‐grade fever, malignant lymphoma	1+1+1 (21)	0+0+0 (21)
Horita 2007	Steroids + RAS inhibitors versus steroids	Hypotension	2 (20)	0 (20)
Hou 2017	MMF versus prednisone	Pneumonia, acute kidney injuries, ophthalmos‐neuritis, osteonecrosis of the femoral head, ESKD, gastric perforation, newly diagnosed diabetes, impaired glucose tolerance, infections, hepatic dysfunction, gastrointestinal symptoms, cushing syndrome, acne, cramps, insomnia, alopecia, tremors	3+1+1+0+0+0+1+12+27+9+7+16+2+5+12+5+5 (87)	4+0+0+1+1+1+12+15+20+14+10+42+5+11+17+11+7 (88)
Julian 1993	Steroids versus no treatment	Overt diabetes, insomnia, acne	2+2+3 (18)	1 (17)
Kanno 2003	Steroids versus warfarin	None reported	0 (6)	0 (4)
Katafuchi 2003	Steroids + dipyridamole versus dipyridamole (in an abstract (Katafuchi 1997) that reported steroids versus antiplatelet agent in 80 participants, no adverse events were reported)	Palpitations/insomnia	3 (43)	1 (47)
Kawamura 2014	Methylprednisolone + tonsillectomy versus steroid	None reported	0 (33)	0 (39)
Lee 2003	Steroids + ARB versus ARB	Not reported	Not reported	Not reported
Kim 2013b	Tacrolimus versus placebo	Cardiovascular, gastrointestinal, genitourinary, hematologic, musculoskeletal, neurologic, respiratory, dermatologic	2+21+4+1+3+12+4+2 (20)	1+4+0+0+3+1+5+1 (20)
Kobayashi 1996	Steroids versus no treatment	None reported	0 (20)	0 (26)
Koike 2008	Prednisolone + dipyridamole versus dipyridamole	None reported	0 (24)	0 (24)
Koitabashi 1996	Chinese medicine (Saireito) versus no treatment versus prednisolone + AZA + anticoagulants + dipyridamole versus anticoagulants + dipyridamole	Not reported	Not reported	Not reported
Lafayette 2017	Rituximab versus usual care	Cough, fever, flu, gastrointestinal symptoms, embolism, infections, rush, nasal congestion, eye problems, wart left 5th digit, right flank tenderness, headache, haemorrhage, pruritus, confusion, fatigue, muscle problems, back pain, dyspnoea, heartburn and cardiac problems, anorexia, sore throat, flushing, hypertension, photosensitivity, vaginal bleeding, left hand numbness	Not reported (17)	Not reported (17)
Lai 1986	Steroids versus no treatment	Gastritis, hypertension	1+3 (17)	0+0 (17)
Lai 1987	CSA versus placebo	Dyspepsia, headache, hypertension, hirsutism	6+7+1+3+7 (12)	0+0+0+0+1 (12)
Liu 2010a	Prednisone + leflunomide versus prednisone + MMF	Not reported	Not reported	Not reported
Liu 2014	Methylprednisolone + CSA versus methylprednisolone	Severe pneumonia, recurrent urinary tract infection, elevated blood sugar,  eyesight degradation	3+2+2+5 (23)	1+3+2+9 (25)
Locatelli 1999	Steroids + AZA versus steroids	Hepatotoxicity, leukopenia, GI symptoms, bacterial Infections, viral Infections, Pneumocystis carinii infection, type 2 diabetes, hypertension	5+3+3+3+1+1+1+0 (101)	0+0+0+2+1+0+2+1 (106)
Lou 2006	Leflunomide versus RAS inhibitors	Serum transaminases, mild alopecia, severe diarrhoea, cough	2+1+1+0 (24)	0+0+0+2 (22)
Lv 2009	Steroids + RAS inhibitors versus RAS inhibitors	Cough, hyperkalaemia, palpitation, arthralgia	2+0+1+1 (33)	1+0+0+0 (30)
Maes 2004	MMF versus placebo	Reactivation of pulmonary TB, gastrointestinal complaints, leukopenia, rectal carcinoma	1+2+1+0 (21)	0+0+0+1 (19)
Manno 2001	Steroids + RAS inhibitors versus RAS inhibitors	Striae, glucidic intolerance, cough	3+1+0 (48)	0+0+2 (49)
Masutani 2016	Prednisolone followed by mizoribine versus prednisolone	Pneumonia, herpes zoster, severe drug allergy	2+0+0 (20)	0+1+1 (20)
Min 2017	Leflunomide + prednisone versus full dose prednisone	Hepatotoxicity, upper respiratory infection, pulmonary infection, diarrhoea, herpes‐zoster virus infection, pruritus, insomnia, alopecia, abnormal glucose metabolism	3+4+2+1+0+1+0+1+0 (40)	2+4+1+0+2+0+2+0+2 (45)
NA IgAN 1995	Steroids versus placebo	Heartburn, increased appetite, weight gain	15+24+22 (33)	5+10+13 (31)
NEFIGAN 2017	Low dose TRF‐budesonide versus high dose TRF‐budesonide versus placebo	Nasopharyngitis, acne, joint swelling, cushingoid, insomnia, diarrhoea, dyspepsia, headache, alopecia, back pain, mood swings, oedema peripheral, blood creatine  phosphokinase increased, hirsutism, hypertension, muscle spasms, abdominal pain, nausea, upper respiratory tract  infection	Treatment group 1 8+8+8+5+6+1+2+3+4+6+3+2+3+3+3+5+4+4+2 (51) Treatment group 2 10+9+9+8+8+5+7+6+4+3+5+6+3+5+5+2+3+3+3 (49)	10+3+2+3+2+7+4+3+2+1+2+2+3+1+1+2+1+1+3 (50)
Ni 2005	Steroids + leflunomide versus steroids	Elevated liver enzyme, infection, diarrhoea, nausea, rash, insomnia, blood glucose increase	4+8+2+1+1+0+0 (51)	4+10+0+0+1+1+1 (51)
Nuzzi 2009	Steroids versus no treatment	None reported	0 (15)	0 (12)
Pozzi 1999	Steroids versus no treatment	None reported	0 (43)	0 (43)
Segarra 2006	Immunoglobulin + steroids versus steroids	Cutaneous rush, DM	1+0 (19)	0+1 (17)
Shen 2013	Corticosteroid + CPA versus corticosteroid + tacrolimus versus corticosteroid	Not reported	Not reported	Not reported
Shi 2012a	Steroids + leflunomide versus steroids	Adverse events were assessed but not clearly reported	Not reported	Not reported
Shima 2018	Prednisolone + mizoribine + warfarin + dipyridamole versus prednisolone + mizoribine	Obesity, hyperuricaemia, hypertension, headache, steroid‐induced gastric ulcer, glaucoma, steroid acne, stretch marks, bleeding, decreased bone mineral density, cataract, elevation of serum bilirubin, psychosis	6+2+1+6+2+2+2+1+2+0+0+0+0	7+5+6+0+3+2+2+1+0+1+1+1+1
Shoji 2000	Steroids versus dipyridamole	Headache	0 (11)	1 (8)
Stangou 2011	AZA + methylprednisolone versus methylprednisolone	Not reported	Not reported	Not reported
STOP‐IgAN 2008	Methylprednisolone versus no treatment	Diverticulitis or appendicitis, pneumonia or respiratory tract infection, viral exanthema, knee empyema, death, malignant neoplasm, impaired glucose tolerance or DM, gastrointestinal bleeding, fracture, osteonecrosis, weight gain	3+3+1+1+1+2+9+0+1+0+14 (82)	1+1+1+0+1+0+1+0+0+0+5 (80)
Takeda 1999	Steroids + antiplatelet agent versus antiplatelet agent	None reported	0 (13)	0 (12)
Tang 2005	MMF + RAS inhibitors versus RAS inhibitors	Fall in haemoglobin level, diarrhoea, upper gastrointestinal upset, infective episodes	3+1+1+3 (20)	None reported (20)
TESTING 2017	Methylprednisolone versus placebo	Respiratory infection, pneumocystis pneumonia, cryptococcal meningitis, nocardia infection of skin and knee joint, perianal abscess, urinary tract infection, fever, duodenal ulcer, gastrointestinal bleeding, gastric perforation, vascular necrosis, osteochondroma, pulmonary embolism, deep vein thrombosis, hepatotoxicity, haemoptysis, acute right upper quadrant pain, arthralgia, symptomatic incarcerated paraumbilical hernia, uremia, soft tissue injury, new‐onset DM, vascular necrosis, fracture	4+3+1+1+1+1+1+1+2+1+2+1+1+2+1+1+1+1+0+0+ 1+2+1+1 (136)	0+0+0+0+0+0+0+0+0+1+0+0+0+0+0+0+0+0+1+2+ 0+3+0+0 (126)
Walker 1990a	CPA + dipyridamole + warfarin versus no treatment	Gonadal toxicity, headache	2+1 (25)	0+0 (27)
Welch 1992	Steroids versus placebo	None reported	0 (20)	0 (20)
Woo 1987	CPA + dipyridamole + warfarin versus no treatment	Gum bleeding	2 (27)	0 (21)
Wu 2016	Telmisartan + clopidogrel placebo + leflunomide placebo versus telmisartan + clopidogrel + leflunomide placebo versus telmisartan + clopidogrel placebo + leflunomide versus telmisartan + clopidogrel + leflunomide	Death, abnormal liver function, hypotension, hyperkalaemia, neutropenia, rash, skin purpura, upper gastrointestinal bleeding, herpes zoster, urinary tract infection, upper respiratory tract infection	Treatment group 1 0+0+0+1+1+0+0+0+1+0+1 (100) Treatment group 2 0+3+1+2+0+0+0+0+0+1+0 (100) Treatment group 3 0+1+2+1+0+0+0+0+0+0+0 (100)	0+3+0+0+2+2+1+1+0+0+0 (99)
Xie 2011	Mizoribine versus losartan versus combination group	Serious adverse events, hyperuricaemia, upper respiratory tract infection,  herpes zoster, leukopenia, elevation of transaminases, vertigo, alopecia	Treatment group 1 0+3+1+0+1+1+0+0 (35) Treatment group 2 0+1+3+0+1+1+1+0 (30)	0+3+2+1+0+0+1+1 (34)
Yoshikawa 1999	Steroids + AZA + dipyridamole versus dipyridamole	Alopecia, anaemia, leukopenia, cataract, ulcer, depression	1+0+3+1+1+1 (40)	0+1+0+0+0+0 (38)
Yoshikawa 2006	Steroids + dipyridamole + AZA + warfarin versus steroids	Hypertension, glucosuria, aseptic necrosis of femur, glaucoma, cataract, headache, leukopenia, bleeding, anaemia, elevated transaminase concentration	0+0+1+2+0+3+3+1+1+2 (40)	5+3+1+2+2+0+0+0+0+1 (40)
Zhang 2004	Leflunomide versus steroids	Elevate liver enzyme, nausea, lose hair, leukopenia	3+1+1+1 (27)	None reported (22)

Date	Event	Description
9 September 2019	New search has been performed	Search update and update of included studies and outcome data
9 September 2019	New citation required and conclusions have changed	New studies and interventions added
15 July 2015	New search has been performed	Review updated
15 July 2015	New citation required and conclusions have changed	New interventions identified
22 July 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	MeSH descriptor Glomerulonephritis, IGA explode all trees in MeSH products iga next glomeruloneph* in Clinical Trials iga next nephropath* in Clinical Trials IgAGN in Clinical Trials ("iga‐n" or "igan") in Clinical Trials berger* next disease* in Clinical Trials ("immunoglobulin a" next nephropath*) in Clinical Trials (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
MEDLINE	Glomerulonephritis, IGA/ iga glomerulonephritis.tw. iga nephropath$.tw. IgAGN.tw. igA‐N.tw. berger$ disease.tw. immunoglobulin a nephropathy.tw. or/1‐7
EMBASE	Immunoglobulin a Nephropathy/ iga nephropathy.tw. iga glomerulonephritis.tw. berger$ disease.tw. IgAGN.tw. igA‐N.tw. immunoglobulin a nephropathy.tw. or/1‐7

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ESKD	8	741	Risk Ratio (IV, Random, 95% CI)	0.39 [0.23, 0.65]
1.1 Steroid (oral) versus placebo or usual care	5	495	Risk Ratio (IV, Random, 95% CI)	0.48 [0.27, 0.85]
1.2 Steroid (IV + oral) versus placebo or usual care	1	86	Risk Ratio (IV, Random, 95% CI)	0.14 [0.01, 2.68]
1.3 Steroid (oral) plus RASi versus RASi alone	2	160	Risk Ratio (IV, Random, 95% CI)	0.16 [0.04, 0.59]
2 Complete remission	4	305	Risk Ratio (IV, Random, 95% CI)	1.76 [1.03, 3.01]
2.1 Steroid (oral) versus placebo or usual care	2	145	Risk Ratio (IV, Random, 95% CI)	3.47 [0.71, 17.08]
2.2 Steroid plus RASi versus RASi alone	2	160	Risk Ratio (IV, Random, 95% CI)	1.41 [0.80, 2.48]
3 Doubling of serum creatinine	7	404	Risk Ratio (IV, Random, 95% CI)	0.43 [0.29, 0.65]
3.1 Steroid (oral) versus placebo or usual care	6	341	Risk Ratio (IV, Random, 95% CI)	0.45 [0.29, 0.69]
3.2 Steroid (oral) plus RASi versus RASi alone	1	63	Risk Ratio (IV, Random, 95% CI)	0.26 [0.06, 1.15]
4 Serum creatinine	7		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 Steroid versus no treatment or placebo or other non‐immunosuppressive treatment	7	211	Mean Difference (IV, Random, 95% CI)	‐21.07 [‐44.12, 1.99]
5 GFR loss: ≥ 50%	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
5.1 Steroid (oral) versus placebo or usual care	2	326	Risk Ratio (IV, Random, 95% CI)	0.56 [0.25, 1.24]
6 Annual GFR loss [mL/min/1.73 m²]	2	359	Mean Difference (IV, Random, 95% CI)	‐5.40 [‐8.55, ‐2.25]
6.1 Steroid (oral) versus placebo or usual care	1	262	Mean Difference (IV, Random, 95% CI)	‐5.16 [‐9.79, ‐0.53]
6.2 Steroid (oral) plus RASi versus RASi alone	1	97	Mean Difference (IV, Random, 95% CI)	‐5.61 [‐9.91, ‐1.31]
7 GFR (any measure)	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.1 Steroid versus no treatment or placebo or other non‐immunosuppressive treatment	4	138	Mean Difference (IV, Random, 95% CI)	17.87 [4.93, 30.82]
8 Urinary protein excretion	10	705	Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.84, ‐0.33]
8.1 Steroid plus dipyridamole versus dipyridamole alone	1	48	Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.78, 0.04]
8.2 Steroid versus no treatment or placebo or other non‐immunosuppressive treatment	9	657	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.92, ‐0.33]
9 Death (any cause)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
9.1 Steroid (oral) versus placebo or usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
10 Infection	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
10.1 Steroid (oral) versus placebo or usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
11 Malignancy	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
11.1 Steroid (IV + oral) versus placebo or usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ESKD	7	463	Risk Ratio (IV, Random, 95% CI)	0.63 [0.33, 1.20]
1.1 Cyclophosphamide then azathioprine plus steroid versus usual care	2	200	Risk Ratio (IV, Random, 95% CI)	0.49 [0.14, 1.75]
1.2 Cyclophosphamide plus antiplatelet/anticoagulant versus usual care	2	100	Risk Ratio (IV, Random, 95% CI)	0.31 [0.03, 2.85]
1.3 Azathioprine plus steroid versus placebo/usual care	1	43	Risk Ratio (IV, Random, 95% CI)	3.14 [0.13, 72.96]
1.4 Azathioprine plus steroid versus steroid alone	1	46	Risk Ratio (IV, Random, 95% CI)	1.17 [0.59, 2.32]
1.5 Azathioprine plus steroid plus anticoagulant/antiplatelet versus anticoagulant/antiplatelet	1	74	Risk Ratio (IV, Random, 95% CI)	0.34 [0.07, 1.64]
2 Complete remission	5	381	Risk Ratio (IV, Random, 95% CI)	1.47 [0.94, 2.30]
2.1 Cyclophosphamide then azathioprine plus steroid versus usual care	1	162	Risk Ratio (IV, Random, 95% CI)	3.41 [1.17, 9.93]
2.2 Cyclophosphamide plus steroid versus steroid	1	24	Risk Ratio (IV, Random, 95% CI)	0.78 [0.44, 1.39]
2.3 Azathioprine plus steroids versus placebo/usual care	1	43	Risk Ratio (IV, Random, 95% CI)	5.94 [2.03, 17.34]
2.4 Azathioprine plus steroids plus anticoagulants versus steroids alone	1	78	Risk Ratio (IV, Random, 95% CI)	1.24 [1.01, 1.52]
2.5 Azathioprine plus steroid plus anticoagulant/antiplatelet versus anticoagulant/antiplatelet	1	74	Risk Ratio (IV, Random, 95% CI)	1.13 [0.76, 1.70]
3 Annual GFR loss [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Cyclophosphamide then azathioprine plus steroid versus usual care	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 GFR (any measure) [mL/min/1.73 m²]	3	174	Mean Difference (IV, Random, 95% CI)	3.07 [‐6.57, 12.72]
4.1 Azathioprine plus steroid plus anticoagulant/antiplatelet versus anticoagulant/antiplatelet	1	74	Mean Difference (IV, Random, 95% CI)	2.0 [‐15.98, 19.98]
4.2 Azathioprine plus steroids plus anticoagulants versus steroids alone	2	100	Mean Difference (IV, Random, 95% CI)	3.51 [‐7.92, 14.94]
5 Urinary protein excretion	5	255	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.80, 0.26]
5.1 Cytotoxic agents plus steroids versus placebo, no treatment or anticoagulant/antiplatelet	3	155	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐2.71, 0.21]
5.2 Cytotoxic agents plus steroids plus anticoagulants versus steroids alone	2	100	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.09, 0.05]
6 Death (any cause)	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
6.1 Cyclophosphamide then azathioprine plus steroid versus steroid	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7 Infection	4	268	Risk Ratio (IV, Random, 95% CI)	1.70 [0.43, 6.76]
7.1 Cyclophosphamide then azathioprine plus steroid versus usual care	2	200	Risk Ratio (IV, Random, 95% CI)	4.65 [0.54, 39.85]
7.2 Azathioprine plus steroid versus steroid alone	2	68	Risk Ratio (IV, Random, 95% CI)	0.85 [0.14, 5.10]
8 Malignancy	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
8.1 Cyclophosphamide then azathioprine plus steroid versus usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ESKD	4	280	Risk Ratio (IV, Random, 95% CI)	0.73 [0.16, 3.23]
1.1 MMF versus placebo/usual care	2	66	Risk Ratio (IV, Random, 95% CI)	2.37 [0.63, 8.96]
1.2 MMF plus steroid versus steroid alone	1	174	Risk Ratio (IV, Random, 95% CI)	0.20 [0.01, 4.20]
1.3 MMF plus RASi versus RASi alone	1	40	Risk Ratio (IV, Random, 95% CI)	0.22 [0.05, 0.90]
2 Complete remission	4	271	Risk Ratio (IV, Random, 95% CI)	1.05 [0.73, 1.52]
2.1 MMF versus placebo/usual care	3	97	Risk Ratio (IV, Random, 95% CI)	2.02 [0.55, 7.38]
2.2 MMF plus steroid versus steroid alone	1	174	Risk Ratio (IV, Random, 95% CI)	0.99 [0.68, 1.46]
3 Doubling of serum creatinine	2	74	Risk Ratio (IV, Random, 95% CI)	2.01 [0.28, 14.44]
3.1 MMF versus placebo/usual care	1	34	Risk Ratio (IV, Random, 95% CI)	4.45 [0.25, 79.87]
3.2 MMF plus RASi versus RASi alone	1	40	Risk Ratio (IV, Random, 95% CI)	1.0 [0.07, 14.90]
4 Serum creatinine	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5 GFR loss: ≥ 50%	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.1 MMF versus placebo/usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 GFR loss: ≥ 25%	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
6.1 MMF versus placebo/usual care	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7 Annual GFR loss [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
7.1 MMF versus placebo/usual care	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 GFR (any measure) [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9 Urinary protein excretion	5	172	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.92, 0.81]
9.1 MMF versus placebo	3	92	Mean Difference (IV, Random, 95% CI)	0.59 [0.20, 0.98]
9.2 MMF plus RASi versus RASi alone	1	40	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐1.46, ‐1.06]
9.3 MMF versus leflunomide	1	40	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.20, 0.16]
10 Infection	4	301	Risk Ratio (IV, Random, 95% CI)	1.36 [0.87, 2.12]
10.1 MMF versus placebo/usual care	3	126	Risk Ratio (IV, Random, 95% CI)	1.35 [0.50, 3.64]
10.2 MMF plus steroid versus steroid alone	1	175	Risk Ratio (IV, Random, 95% CI)	1.37 [0.83, 2.24]
11 Malignancy	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
11.1 MMF versus placebo/usual care	2	86	Risk Ratio (IV, Random, 95% CI)	0.28 [0.03, 2.54]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete remission	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
1.1 CNI plus steroid versus steroid	2	72	Risk Ratio (IV, Random, 95% CI)	0.91 [0.60, 1.39]
2 Serum creatinine	2	62	Mean Difference (IV, Random, 95% CI)	7.75 [‐6.76, 22.27]
2.1 Cyclosporin versus placebo or usual care	1	22	Mean Difference (IV, Random, 95% CI)	0.0 [‐32.39, 32.39]
2.2 Tacrolimus versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	9.70 [‐6.53, 25.93]
3 GFR (any measure)	3	110	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐7.42, 7.07]
3.1 Cyclosporin versus placebo or no treatment [mL/min/1.73 m²]	1	22	Mean Difference (IV, Random, 95% CI)	4.5 [‐7.36, 16.36]
3.2 Tacrolimus versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	‐5.70 [‐20.27, 8.87]
3.3 CNI plus steroid versus steroid	1	48	Mean Difference (IV, Random, 95% CI)	‐1.17 [‐12.92, 10.58]
4 Urinary protein excretion	3	110	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐1.12, 0.12]
4.1 Cyclosporin versus placebo or no treatment	1	22	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐2.43, ‐0.77]
4.2 Tacrolimus versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.52, 0.30]
4.3 CNI plus steroid versus steroid	1	48	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.46, 0.12]
5 Infection	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
5.1 CNI plus steroid versus steroid	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Malignancy	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected
6.1 CNI plus steroid versus steroid	1		Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete remission	2	115	Risk Ratio (IV, Random, 95% CI)	1.05 [0.83, 1.31]
1.1 Steroid plus RASi versus steroid alone	1	38	Risk Ratio (IV, Random, 95% CI)	1.08 [0.84, 1.39]
1.2 Steroid plus tonsillectomy plus ARB versus steroid plus tonsillectomy	1	77	Risk Ratio (IV, Random, 95% CI)	0.93 [0.56, 1.53]
2 GFR (any measure) [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Steroid plus RASi versus steroid alone	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Urinary protein excretion	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Steroid plus RASi versus steroid alone	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Methods	Study design: parallel, 2‐arm RCT Time frame Study start date: January 2002 Primary completion date: March 2008 Actual completion date: March 2010 Duration of follow‐up: 12 months
Participants	Setting: multicentre (30 sites) Country: USA and Canada Inclusion criteria: aged 7 to 70 years, kidney biopsy diagnostic for IgAN based on mesangial immunofluorescence staining for IgA ≥ IgG and IgM, UPCR 0.6 ≥ g/g (males) or ≥ 0.8 g/g (females), and eGFR ≥ 50 mL/min/1.73 m² (or ≥ 40 mL/min/1.73 m² in those already receiving an ACEi or ARB) Number (analysed/randomised): treatment group (13/25); treatment group (15/27) Mean age ± SD (years): treatment group (31.8 ± 11.7); control group (32.2 ± 13.2) Sex (M/F): treatment group (14/11); control group (18/9) Exclusion criteria: SLE; HSP; chronic liver disease or hepatitis; history of significant gastrointestinal disorder; HIV infection; any systemic infection; absolute neutrophil count < 2000/μL; HCT < 28%; known contraindication to MMF, highly purified omega‐3 fatty acid, or lisinopril (or losartan if used instead of lisinopril); other major organ system disease or malignancy; current or prior treatment with MMF or AZA; pregnancy or breast‐feeding at time of entry or unwillingness to comply with measures for contraception; and current or recent exposure to any investigational drug
Interventions	Treatment group MMF: maximum 1 g twice/day. Initial dose for the first 2 weeks of therapy was approximately one‐half to two‐thirds of the full dose. The target dose was 25 to 36 mg/kg/day for 12 months. The dose was reduced if a person developed gastrointestinal toxicity, HCT < 25%, or absolute neutrophil count was 1000 to 1500/μL. The study drugs were discontinued if these problems persisted or in the event of pregnancy, refusal to maintain contraception, non adherence to the protocol, or decrease in eGFR ≥ 40% from study entry Control group Placebo Co‐interventions Lisinopril (or losartan) plus a highly purified omega‐3 fatty acid
Outcomes	eGFR < 60% of the baseline level (estimated with the Schwartz (age < 18 years) or Cockcroft‐Gault (age ≥ 18 years) formula) Annual change in eGFR UPCR Malignancy Complete remission (UPCR < 0.3 g/g) Partial remission (UPCR decreased ≥ 50%) Adverse events Serious adverse events
Notes	This study was supported by an unrestricted grant from Roche Laboratories Inc Trials registration identification number: NCT00318474 The trial was conducted under an investigator‐initiated Investigational New Drug application (Funding Opportunity Announcement number 48,977) in US centres, and with the approval of Health Canada (Bureau of Pharmaceutical Assessment [BPA] control number 076948) in Canadian sites
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised scheme that was constructed with a computer‐based pseudo‐random number generator
Allocation concealment (selection bias)	Unclear risk	The biostatistician determined the treatment group assignment for all eligible patients
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind placebo‐controlled study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation. Reporting of adverse events may have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	High risk	12/25 participants assigned to MMF (fall in GFR (2); patient choice (2); prolonged hospitalisation (1); non‐adherence (1); trial termination (6)) and 12/27 participants assigned to placebo (loss‐to‐follow up (1); patient choice (4); malignant melanoma (1); pregnancy (1); trial terminated (5)) did not complete study at 12 months
Selective reporting (reporting bias)	High risk	Key outcomes expected for this type of study (death (any cause) and ESKD) were not reported
Other bias	High risk	An independent Data and Safety Monitoring Committee met in person or by teleconference at least annually. In year 5 of the trial (2007), following careful consideration of the unblinded trial data, the committee concluded that it was extremely unlikely that any efficacy could be demonstrated from the limited additional enrolment and follow‐up that was going to be possible. The committee therefore recommended termination of the trial. There were no safety issues leading to this decision. Baseline characteristics were balanced across treatment groups

Methods	Study design: parallel, 2‐arm quasi‐RCT Time frame: April 1972 to December 1983 (patient diagnosis) Duration of follow‐up: 10 years
Participants	Setting: single renal unit Country: Japan Inclusion criteria: primary diagnosis of IgAN, proteinuria between 1 to 2 g/d; CrCl ≥ 70 mL/min; histological severity score ≥ 7 Number (analysed/randomised): treatment group (20/31); control group (26/59) Mean age ± SD (years): treatment group (30 ± 7); control group (33 ± 10) Sex (M/F): treatment group (12/8); control group (12/14) Exclusion criteria: not reported
Interventions	Treatment group Prednisolone: 40 mg/d for 3 weeks, 30, 25 and then 20 mg/d for 8 weeks; maintained at 15 mg/d for 6 months and then further tapered (most of the patients received steroid therapy for 18 months) Antithrombocyte drugs were prescribed after discontinuation of steroid therapy until final observation Control group Antithrombocyte drugs until final observation Co‐interventions Not reported
Outcomes	ESKD CrCl Urinary protein excretion
Notes	Funding: supported by grants from the Ministry of Health and Welfare, Japan Trials registration identification number: not applicable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Prospectively divided into two groups according to the order of renal biopsy
Allocation concealment (selection bias)	High risk	Prospectively divided into two groups according to the order of renal biopsy. This is a quasi‐randomised study design
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	High risk	11/31 patients in the treatment group and 33/59 patients from the control group were excluded from the analyses
Selective reporting (reporting bias)	High risk	Key outcomes expected for this type of study (death (any cause), malignancy, infection) were not reported
Other bias	High risk	The participants received differential prescribing of anti‐thrombotic drugs during follow‐up. There was imbalance in sex and history of hypertension at baseline

Methods	Study design: parallel, 4‐arm RCT Time frame: November 2010 to June 2011 Duration of follow‐up: 4 months
Participants	Setting: multicentre (40 sites) Country: Japan Inclusion criteria: IgAN; aged < 15 years; no administration of steroids nor immunosuppressive drugs; no functionally disordered; diffuse proliferative GN Number (analysed/randomised): 115/not reported Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group 1 Chinese medicine (Saireito) in children with minor renal histology abnormalities or focal and segmental proliferative GN Treatment group 2 No treatment in children with minor renal histology abnormalities or focal and segmental proliferative GN Treatment group 3 Prednisolone + AZA + anticoagulants + dipyridamole in children with diffuse proliferative GN Control group Anticoagulants + dipyridamole in children with diffuse proliferative GN Co‐intervention: not reported
Outcomes	Proteinuria Haematuria Kidney function Renal histopathological findings
Notes	Conference abstract Funding: not reported Trials registration identification number: not applicable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	There was no pre‐specified protocol identified for this study. The study did not report extractable data for the key outcomes that would be expected for a study of this type (e.g., death (any cause), GFR loss, infection, malignancy)
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel, 2‐arm RCT Duration of study: January 2004 to September 2006 Duration of follow‐up: 48 months
Participants	Setting: single centre Country: China Inclusion criteria: biopsy‐proven IgAN aged 18 to 65 years; proteinuria 1 to 5 g/d on 3 consecutive measurements 4 to 6 weeks apart; eGFR > 30 mL/min/1.73 m² Number (analysed/randomised): treatment group (31/33); control group (29/30) Mean age ± SD (years): treatment group (27.8 ± 8.9); control group (30.43 ± 8.8) Sex (M/F): treatment group (20/13); control group (19/11) Exclusion criteria: treatment with steroids or cytotoxic drugs during the previous year; pregnancy or planning pregnancy; HSP; DM; neoplasia; active peptic ulcer disease; viral hepatitis; infection
Interventions	Treatment group Prednisone: 0.8 to 1.0 mg/kg/day, for 8 weeks, then the dose was tapered by 5 to 10 mg every 2 weeks Cilazapril: 5 mg/day for 24 months Control group Cilazapril: 5 mg/day for 24 months Co‐interventions Not reported
Outcomes	ESKD (CKD stage 5) Remission of proteinuria 25% decrease in eGFR 50% increase in SCr Mean arterial pressure Urine protein excretion 50% decrease in protein excretion Major adverse events Serious infections
Notes	Funding: "This work was funded by the National Natural Science Foundation of China (Grant No. 30670981), the Foundation of Ministry of Education (985‐2‐2007‐113), and National Key Technology R & D Progression (2007 BAI04B10), People’s Republic of China." Trials registration identification number: NCT00378443
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation code
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation. However, reporting of adverse events may have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2/33 participants withdrawn from combination group and 1/30 withdrawn from control group
Selective reporting (reporting bias)	Low risk	All relevant outcomes that would be expected in a study of this type, except mortality, were reported
Other bias	Low risk	The study appeared to be free of other sources of bias

Methods	Study design: parallel, 3‐arm RCT Time frame: not reported Duration of follow‐up: 24 months
Participants	Setting: multicentre (37 centres; 44 centres were described in study protocol) Country: USA Inclusion criteria: < 40 years, able to swallow 500 mg placebo tablet; eGFR ≥ 50 mL/min/1.73 m²; persistent severe proteinuria; biopsy‐proven IgAN within 3 years of entry Number (analysed/randomised): treatment group (not reported/33); control group 1 (not reported/32); control group 2 (not reported/31) Mean age ± SD (years): treatment group (24 ± 10); control group 1 (20 ± 10); control group 2 (21 ± 10) Sex (M): treatment group (70%); control group 1 (66%); control group 2 (65%) Exclusion criteria: SLE; HSP nephritis; abnormal liver function; pregnancy or unwilling to use appropriate contraception; diabetes; cataracts; aseptic necrosis of any bone; use of study agents in the 3 months prior to entry
Interventions	Treatment group Prednisone: 60 mg/m² on alternate days for 3 months, 40 mg/m² on alternate days for 9 months, 30 mg/m² on alternate days for 12 months Control group 1 Fish oil: up to 4 g/d for 2 years Control group 2 Placebo: half received fish oil placebo and half received prednisone placebo Co‐interventions Not reported
Outcomes	Time to kidney failure (decrease in CrCl ≤ 60% baseline value) Adverse events
Notes	Funding: "Supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK49368. Medications that were used in this trial were generously donated by Merck and Co. Inc. (enalapril), Pharmacia and Upjohn (prednisone [Deltasone] and matching placebo), and Pronova Biocare (Omacor and matching placebo)." Trials registration identification number: not applicable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation. However, reporting of adverse events may have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	High risk	Quote: "72 completed 2 years of trial drugs and 18 patients exited prematurely. Six patients dropped out of the trial after randomisation but before the start of study drugs."
Selective reporting (reporting bias)	High risk	The primary outcome was changed between the protocol (CrCl < 70% of baseline value) and the final study publication (CrCl <of 60% of baseline value)
Other bias	High risk	Interim analyses were planned but not clearly reported. The methods for interim analyses were different in the protocol and the final study publication. Imbalance at baseline for level of proteinuria between study groups

Methods	Study design: 2‐group, parallel, group‐sequential RCT Time frame: February 2008 to February 2015 Duration of follow‐up: 36 months
Participants	Setting: multicentre (32 sites) Country: Germany Inclusion criteria: primary IgAN confirmed on biopsy; 18 to 70 years; proteinuria level > 0.75 g/day of urinary protein excretion plus arterial hypertension (defined by the use of antihypertensive medication or by an ambulatory BP ≥ 140/90 mmHg), impaired kidney function (defined as an eGFR < 90 mL/min/1.73 m²), or both Number (analysed/randomised): treatment group (80/80); control group (82/82) Mean age ± SD (years): treatment group (45.8 ± 12.5); control group (42.8 ± 13.1) Sex (M/F): treatment group (61/19); control group (56/24) Exclusion criteria: eGFR < 30 mLmin/1.73 m²; secondary and rapidly progressive, crescentics IgAN; other CKDs; any prior immunosuppressive therapy
Interventions	Treatment group Patients with GFR of at least 60 mL/min/1.73 m² Methylprednisolone (IV): 1 g/ day for 3 days at the start of months 1, 3, and 5; and oral prednisolone at a dose of 0.5 mg/kg per 48 hours on the other day Patients with an eGFR between 30 and 59 mL/min/1.73 m² CPA: 1.5 mg/kg/day for 3 months, followed by AZA at a dose of 1.5 mg/kg/day during months 4 through 36 Prednisolone (oral): 40 mg/day, tapered to 10 mg/day, over the first 3 months of the study, 10 mg/day during months 4 through 6, and 7.5 mg/day during months 7 through 36 months Control group No treatment Co‐interventions Comprehensive supportive care that included blockers of the RAS to lower BP to a target below 125/75 mm Hg. If proteinuria remained above the target of 0.75 g/day of urinary protein excretion despite blood‐pressure control, the dose of RAS blocker was increased to the maximum approved daily dose or to the highest dose at which the patient did not have unacceptable side effects. Patients received dietary counselling and were advised to quit smoking and to avoid nonsteroidal antiinflammatory drugs and other nephrotoxins. Total cholesterol levels were lowered to < 200 mg/dL (5.2 mmol/L) with the use of statins, if necessary
Outcomes	Complete remission: defined as proteinuria with a UPCR of < 0.2 and stable kidney function with a decrease in GFR of < 5 mL/min/1.73 m² from the baseline eGFR at the end of the 3‐year trial phase GFR loss of 15 mL/min or higher from baseline GFR GFR loss ≥ 30 mL/min from baseline Annual change in slope of the reciprocal of SCr Proteinuria Disappearance of microhaematuria ESKD death (any cause) Adverse events including malignancy/infection
Notes	The study was funded through German Federal Ministry of Education and Research grant GFVT01044604
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Randomisation codes that were used to assign patients in a 1:1 ratio were generated by means of covariate adaptive randomisation with respect to factors that had the potential to modify the treatment effect (i.e., eGFR and proteinuria). Telephone randomisation by the study secretary. After the investigator establishes the eligibility of the patient to participant in the study, the study centre sends a fax to the Trial Office. The Trial Office assigned a treatment to the patient after being sent the following information: initials, gender, age, CrCl, degree of proteinuria
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation. Reporting of adverse events may have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4/82 assigned to immunosuppression were lost to follow up. 4/80 assigned to supportive care were lost to follow up
Selective reporting (reporting bias)	Low risk	All relevant outcomes were reported
Other bias	Low risk	The study appeared to be free of other sources of bias

PERMALINK

Immunosuppressive agents for treating IgA nephropathy

Patrizia Natale

Suetonia C Palmer

Marinella Ruospo

Valeria M Saglimbene

Jonathan C Craig

Mariacristina Vecchio

Joshua A Samuels

Donald A Molony

Francesco Paolo Schena

Giovanni FM Strippoli

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse effects

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Post hoc subgroup analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Systemic corticosteroid versus no corticosteroid regimen for IgA nephropathy.

Summary of findings 2. Cytotoxic regimen versus no cytotoxic regimen for IgA nephropathy.

Summary of findings 3. MMF regimen versus no MMF regimen for IgA nephropathy.

Summary of findings 4. Calcineurin inhibitor regimen versus no calcineurin inhibitor regimen for IgA nephropathy.

Summary of findings 5. Mizoribine regimen versus no mizoribine regimen for IgA nephropathy.

Summary of findings 6. Leflunomide regimen versus no leflunomide regimen for IgA nephropathy.

End‐stage kidney disease requiring kidney replacement therapy

1.1. Analysis.

3.1. Analysis.

4.1. Analysis.

6.1. Analysis.

7.1. Analysis.

Complete remission

Methods	Study design: cross‐over, 2‐arm RCT Time frame: 1983 to 1989 Duration of follow‐up: 24 weeks
Participants	Setting: single centre Country: USA Inclusion criteria: children with IgAN Number (analysed/randomised): 20/20 Mean age: 13 years (SD not reported) Sex (M/F): 15/5 Exclusion criteria: SCr ≥140 µmol/L; hypertension (BP consistently 99th percentile for age and gender)
Interventions	Two, 3‐month courses of therapy separated by a 3‐month rest period Treatment group Prednisolone: 2 mg/kg/day for 2 weeks, then every other day for 10 weeks Control group Placebo: 2 mg/kg/day for 2 weeks, then every other day for 10 weeks Co‐interventions Not reported
Outcomes	Urinary protein excretion SCr
Notes	Funding: not reported Trials registration identification number: not applicable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The first course for each patient was assigned by a random‐numbers table."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "The drugs were dispensed by the Children's Hospital Medical Center pharmacy with a coded label, so that neither patients nor investigators were aware of the identity of the medication."
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in analyses
Selective reporting (reporting bias)	High risk	Relevant numeric data were not available. Patient‐centred outcomes of relevance were not reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: RCT Time frame: September 1990 to December 1997 Duration of follow‐up: mean 41 months
Participants	Setting: not reported Country: Japan Inclusion criteria: patients diagnosed as primary IgA nephropathy. They had a histological diagnosis of IgA nephropathy with immunofluorescence showing mesangial IgA deposits Number (analysed/randomised): overall (not reported/37); treatment group (not reported/17); control group (not reported/20) Mean age ± SD (years): overall (not reported); treatment group (not reported); control group (not reported) Sex (M/F): overall (13/24); treatment group (not reported); control group (not reported) Exclusion criteria: not reported
Interventions	Treatment group IV methylprednisolone: 1g daily for 3 consecutive days Oral prednisolone: for 12 months Control group No steroid treatment Co‐interventions Not reported
Outcomes	ESKD Renal survival (doubling of SCr) Urinary protein excretion Mesangial cell proliferation Mesangial matrix Cellular crescents
Notes	Conference abstract Funding: not reported Trials registration identification number: not applicable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	There was no pre‐specified protocol identified for this study. The study did not report extractable data for the key outcomes that would be expected for a study of this type (e.g., death (any cause), GFR loss, infection, malignancy)
Other bias	Unclear risk	Insufficient information to permit judgement

Study	Reason for exclusion
Chen 2009b	Wrong intervention: not immunosuppressive agent intervention; the study evaluated Tripterygium wilfordii Hook F. This treatment was adjudicated as not immunosuppression
Czock 2007	Wrong intervention: not immunosuppressive agent intervention; the study evaluated the pharmacokinetics of two different mycophenolic acid formulations. As the study did not compare two different immunosuppression agents, this study was adjudicated as not fulfilling the eligibility criteria on the basis of intervention
Dal Canton 2005	This study was abandoned without completing participant recruitment.
GloMY 2010	This study was adjudicated as not completing recruitment target. The study authors let us know that the trial was closed to recruitment on 21 August 2012 with 3 patients with IgAN randomised. The trial was intended as a pilot for feasibility for a larger trial.
Imai 2006	Wrong population: not all participants with biopsy‐proven IgAN; the study included participants with a range of crescentics glomerulopathies. Data for those participants with IgAN were not available separately.
Shen 2009	Wrong intervention: not immunosuppressive agent intervention; the study compared combined regime of Tripterygium glycosides and benazepril. These treatments were adjudicated as not immunosuppression.
Sulimani 2001	Wrong population: not all patients had IgAN; data for those participants with IgAN were not available separately.
Yonemura 2000b	Wrong population: not all participants had IgAN; the study included participants with minimal change disease.

Methods	Single centre parallel RCT
Participants	40 patients with crescentics IgAN
Interventions	Pulse IV CPA or oral MMF
Outcomes	Efficacy, safety, tolerability and relapse of MMF
Notes	Study completed in 2006. Written to investigators to request update/data. As study is completed >10 years previously, trial data are unlikely to be available or obtained.

Methods	Parallel RCT
Participants	Setting: multicentre Country: China Patients with age 14 to 65 years, regardless of gender; clinical evaluation and renal biopsy diagnostic for IgAN, presenting with active pathological changes,including cellular crescents,necrosis and microthrombus; average urinary protein excretion of 0.5 to 3.5 g/24 hours on two successive examinations; eGFR ≥ 50 mL/min/1.73 m² Number: 180 participants planned Mean age ± SD (years): not available Sex (M/F): not available Exclusion criteria: Secondary IgAN such as SLE, HSP; nephritis and hepatitis B ‐associated nephritis; rapidly progressive nephritic syndrome (crescent formation ≥ 50%); AKI, including rapidly progressive IgAN; current or recent (within 30 days) exposure to high‐dose of steroids or immunosuppressive therapy (CPA, MMF, CSA, FK506); date of renal biopsy exceeds more than 30 days; cirrhosis, chronic active liver disease; history of significant gastrointestinal disorders (e.g. severe chronic diarrhoea or active peptic ulcer disease); any active systemic infection or history of serious infection within one month; other major organ system disease (e.g. serious cardiovascular diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma requiring oral steroid treatment or central nervous system diseases); active tuberculosis; malignant hypertension that is difficult to be controlled by oral drugs; known allergy, contraindication or intolerance to the steroids; pregnancy or breast feeding at the time of entry or unwillingness to comply with measures for contraception; malignant tumours; excessive drinking or drug abuse; mental aberrations; current or recent (within 30 days) exposure to any other investigational drugs
Interventions	Treatment group 1 IV methylprednisolone 0.5 g/day for 3 consecutive days in the 1st, 2nd and 3rd month, and then oral methylprednisolone 0.4 mg/kg/day on consecutive days for 6 months Treatment group 2 IV Methylprednisolone 0.5 g/day for 3 consecutive days in the 1st, 3rd and 5th month, and then oral methylprednisolone 0.4 mg/kg/day on consecutive days for 6 months
Outcomes	Remission of proteinuria (complete or partial) Deterioration of kidney function Longitudinal decline of kidney function (eGFR)
Notes	Study completed on December 2016 Emailed investigators on 21.5.2018 to request update on trial status, but not answer was provided Clinicaltrials.gov identifier: NCT02160132 No study results available

Trial name or title	Efficacy and safety of a combination of mycophenolate mofetil and corticosteroid in advanced IgA nephropathy (AIGA)
Methods	Parallel RCT
Participants	Setting: multicentre Country: Korea Inclusion criteria Patients aged 19 to 65 years old Diagnosed with IgAN Confirmed with proteinuria more than 1.0 g/day at least twice within 6 months from the time of screening If eGFR (by MDRD) is < 50 mL/min/1.73 m², ≥15 mL/min/1.73 m²; ACE inhibitor or ARB for at least 3 months Willing and able to provide written informed consent Number: 100 participants planned Mean age ± SD (years): not yet available Sex (M/F): not yet available Exclusion criteria If eGFR (by MDRD) is < 15 mL/min/1.73 m² BP is SBP >160 mmHg or DBP >100 mmHg Systemic infection or have been diagnosed with cancer within the last 5 years (excluding treatment squamous cell or basal cell carcinoma skin cancer)serious digestive disorder; WBC < 3000/mm³ Acute (within 4 weeks) or chronic(need to treatments) allergic/hypersensitivity reaction in the history of Investigational drugs Administration of other Investigational drugs within 28 days before screening period Administration of Investigator drug or other immunosuppressants within 84 days before screening period Women in pregnant or breast‐feeding or don't using adequate contraception Patient has conversation impairment because alcohol or drugs addiction history within 6 months or mental illness In investigator's judgment
Interventions	Treatment group 1 MMF and corticosteroid: MMF less than 80 kg: 1500 mg/day, 80 kg or more: 2000 mg/day divided twice a day and administered orally Treatment group 2 Conservative treatment (ACEi or ARB)
Outcomes	Remission rate (complete/partial) eGFR The incidence of KRT The average time to occurrence of KRT
Starting date	June 2016
Contact information	Eunju Jung oakly74@nate.com; Jonghyuk Lee leejongh@ckdpharm.com
Notes	Study completion date: October 2018 No study results available

Trial name or title	Study of the safety and efficacy of OMS721 in patients with immunoglobulin A (IgA) nephropathy
Methods	Parallel RCT
Participants	Setting: not yet available Country: USA Patients aged 18 years and above with a biopsy‐confirmed diagnosis of IgAN within 10 years, with 24‐hour urinary protein excretion that is > 1 g/day at baseline, eGFR of ≥ 30 and ≤9 0 mL/min/1.73 m², currently on physician‐directed, stable treatment with RAS blockade (ACEI, ARB, direct renin inhibitors) and have a systolic BP of <150 mmHg and a diastolic BP of <100 mmHg at rest Number: approximately 430 patients are to enrolled in two groups of 215 patients per arm Mean age ± SD (years): not yet available Sex (M/F): not yet available Exclusion criteria: Treatment with immunosuppressants (e.g., AZA or CPA), cytotoxic drugs, or eculizumab within 24 weeks prior to screening; unwilling or unable to discontinue systemic corticosteroids 12 weeks prior to randomisation; female patients who are pregnant, breast feeding, or planning to become pregnant up through 12 weeks after the last dose of study drug, including possible re treatments; clinical or biological evidence of DM, systemic lupus erythematosus, IgA vasculitis (HSP), secondary IgAN, or other renal disease; history of renal transplantation; have a known hypersensitivity to any constituent of the investigational product; rapidly progressive GN; significant abnormalities in clinical laboratory values; BMI ≥ 35 kg/m², history of HIV (HIV), hepatitis B infection and hepatitis C infection; diagnosis of a malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or other cancer from which the patient has been disease‐free for ≥ 5 years; have received any other investigational drug or device or experimental procedures within 30 days of the screening visit
Interventions	Treatment group 1 OMS721 Treatment group 2 Placebo (5% dextrose in water or normal saline solution)
Outcomes	Change from baseline in 24‐hour urine protein excretion in g/day at 24 weeks from beginning of treatment Number of patients with treatment related adverse events as assessed by CTCAE v 4.0 Change from baseline in kidney function as determined by the rate of change in eGFR up to 144 weeks from beginning of treatment Change from baseline in 24‐hour urine protein excretion in g/day at 24 weeks from beginning of treatment in the subset of patients with baseline high proteinuria (defined as 24‐hour urinary protein excretion ≥ 2 g/day) Time‐averaged change in UPCR through 24 weeks
Starting date	February 2018
Contact information	Laura Haas (206) 676‐0886 lhaas@omeros.com Fay Wang (206) 676‐0863 fwang@omeros.com
Notes	Estimated study completion date: April 2023 No study results available

Trial name or title	Prospective study of the efficacy and safety of improved Italy scheme therapy for IgA nephropathy
Methods	Not reported
Participants	Setting: not yet available Country: China Patients with IgAN; histological diagnosis of IgA; nephropathy with immunofluorescence showing mesangial IgA deposits; age between 15 and 75 years; urinary protein excretion of 0.5 to 3.5 g/day; SCr ≤ 171 mol/L (2 mg/dL) Number: not yet available Mean age ± SD (years): not yet available Sex (M/F): not yet available Exclusion criteria: not yet available
Interventions	Treatment group 1 Methylprednisolone Treatment group 2 Methylprednisolone with low dose oral glucocorticoids
Outcomes	24 hours urinary protein eGFR Clearance creatinine Albumin Triglycerides and cholesterol Fasting plasma glucose Uric acid; blood routine test Routine urine
Starting date	Not reported
Contact information	Li Y: Telephon number and email were not reported
Notes	Estimated study completion date: not reported No study results available

Trial name or title	The Effects of mycophenolate mofetil (MMF) on renal outcomes in advanced immunoglobulin A (IgA) nephropathy patients (MAIN)
Methods	Parallel RCT
Participants	Setting: multicentre Country: China Patients with biopsy‐proven primary IgAN with urinary proteinuria excretion over 1g/24 hour, subjects must meet 2 of the following criteria: global glomerular sclerosis plus focal segmental glomerular sclerosis ratio ≥ 50%; eGFR 30 to 60 mL/min; hypertension (BP over 140/90 mmHg or taking antihypertensive drugs) Number: 232 participants planned Mean age ± SD (years): not yet available Sex (M/F): not yet available Exclusion criteria: secondary IgAN; familial IgAN; concomitant disease: cancer, infection, DM, connective tissue disease, abnormal liver function; pregnancy or breasting; inability to comply with study and follow‐up procedures
Interventions	Treatment group 1 MMF: 1.5 g/day and maximum tolerated labelled dose of losartan Treatment group 2 Losartan: maximum tolerated labelled dose
Outcomes	Time to the first occurrence of a component of the composite renal endpoint: doubling of SCr or the onset of ESKD A decrease in eGFR of 30% or ≥ 60 mL/min at the exit visit if the baseline eGFR ≥ 60 mL/min Or a decrease in eGFR ≥ 50% at the exit visit if the baseline eGFR < 60 mL/min
Starting date	June 2013
Contact information	Fan Fan Hou 0086‐20‐61641591 ffhouguangzhou@163.com
Notes	Estimated study completion date: June 2018 No study results available

Trial name or title	Mycophenolate mofetil (MMF) in patients With IgA nephropathy
Methods	Parallel RCT
Participants	Setting: multicentre Country: China Aged 14 to 60 years, regardless of gender; clinical evaluation and renal biopsy diagnostic for IgAN, excluded secondary IgAN. Renal histological criteria should be defined by Lee's glomerular grading system;1 g/day ≤ proteinuria < 3.5 g/day, or UPCR ≥ 0.6 (male) or ≥ 0.8 (female) when taking ARB; eGFR ≥ 40 mL/min/1.73 m² Number: 151 participants planned Mean age ± SD (years): not yet available Sex (M/F): not yet available Exclusion criteria: inability or unwillingness to sign the informed consent; inability or unwillingness to meet the scheme demands raised by the investigators; rapidly progressive nephritic syndrome and AKI, including rapidly progressive IgAN (IgAN with rapid decline in kidney function characterized histologically by necrotizing vasculitis and crescent formation ≥ 30%) necessitating the use of other immunosuppressive agents; secondary IgAN such as SLE, HSP nephritis and hepatitis B ‐associated nephritis; eGFR < 40 mL/min/1.73m²; malignant hypertension that is difficult to be controlled by oral drugs; cirrhosis, chronic active liver disease; history of significant gastrointestinal disorders (e.g. severe chronic diarrhoea or active peptic ulcer disease); any active systemic infection or history of serious infection within one month of entry or known infection with HIV, hepatitis B, or hepatitis C; other major organ system disease (e.g. serious cardiovascular diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma requiring oral steroid treatment or central nervous system diseases); malignant tumours (except fully cured basal cell carcinoma); absolute neutrophil count < 1500/mm³, absolute platelet count < 75,000/mm³ or HCT < 28% (anaemic subjects may be reevaluated after the anaemia has been treated); known allergy, contraindication or intolerance to the MMF, corticosteroids or ACEI/ARB; pregnancy or breast feeding at the time of entry or unwillingness to comply with measures for contraception; current exposure to MMF or AZA. In case of current treatment with oral steroid or ACEI/ARB, entry is permitted after corticosteroids or ACEI/ARB are stopped for 2 weeks; current or recent (within 30 days) exposure to any other investigational drugs
Interventions	Treatment group 1 Prednisone: IV methylprednisolone at a dose of 0.5 g/day for 3 days at the start of months 1, 3, and 5; then take oral prednisone (0.5 mg/kg/day) on alternate days. Prednisone will be tapered 5 mg/month from the 7th to the 12th month Treatment group 2 MMF. 1.0 g twice/day (weight ≥ 50 kg) or 0.75 g twice/day (weight < 50 kg) for the first 6 months of drug treatment phase, then 0.5 g twice/day for the remaining 6 months Treatment group 3 Prednisone: IV methylprednisolone at a dose of 0.5 g/day for 3 days at the start of months 1, 3, and 5; then take oral prednisone (0.5 mg/kg/day) on alternate days. Prednisone will be tapered 5 mg per month from the seventh month to the 12th month. MMF: 1.0 g twice/day (weight ≥ 50 kg) or 0.75 g twice/day (weight < 50 kg) for the first 6 months of drug treatment phase, then 0.5 g twice/day for the remaining 6 months Co‐interventions Irbesartan. In the ARB lead‐in phase, each subject will be on a strict sodium‐restricted diet (< 5 g NaCl/day), and then given a stable dose (150 mg to 300 mg/day) of irbesartan (Aprovel) for 3 months until reaching the target BP level of ≤ 125/75 mmHg. Patients will continue ARB treatment in the drug treatment phase and at least 3 years in the follow‐up phase
Outcomes	Complete remission Deterioration of kidney function
Starting date	September 2007
Contact information	Xueqing Yu 8620‐87766335 yuxq@mail.sysu.edu.cn Qiongqiong Yan 8620‐87755766 ext 8843 qqyzzm@yahoo.com.cn
Notes	Estimated study completion date: April 2019 No study results available