Interventions for minimal change disease in adults with nephrotic syndrome

Karolis Azukaitis; Suetonia C Palmer; Giovanni FM Strippoli; Elisabeth M Hodson

doi:10.1002/14651858.CD001537.pub5

. 2022 Mar 1;2022(3):CD001537. doi: 10.1002/14651858.CD001537.pub5

Interventions for minimal change disease in adults with nephrotic syndrome

Karolis Azukaitis ¹, Suetonia C Palmer ^2,^✉, Giovanni FM Strippoli ^3,⁴, Elisabeth M Hodson ⁴

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC8887628 PMID: 35230699

Abstract

Background

Steroids have been used widely since the early 1970s for the treatment of adult‐onset minimal change disease (MCD). Recently, newer agents have been used in adult MCD aiming to reduce the risk of adverse effects. The response rates to immunosuppressive agents in adult MCD are more variable than in children. The optimal agent, dose, and duration of treatment for the first episode of nephrotic syndrome, or for disease relapse(s) have not been determined. This is an update of a review first published in 2008.

Objectives

We aimed to 1) evaluate the benefits and harms of different agents, including both immunosuppressive and non‐immunosuppressive agents, in adults with MCD causing the nephrotic syndrome; and 2) evaluate the efficacy of interventions on 'time‐to‐remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 21 July 2021 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

Randomised controlled trials (RCTs) and quasi‐RCTs of any intervention for MCD with nephrotic syndrome in adults over 18 years were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non‐immunosuppressive agents were assessed.

Data collection and analysis

Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random‐effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

Fifteen RCTs (769 randomised participants) were identified; four studies evaluated different prednisolone regimens, eight studies evaluated the calcineurin inhibitors (CNIs) (tacrolimus or cyclosporin), two studies evaluated enteric‐coated mycophenolate sodium (EC‐MPS) and one study evaluated levamisole. In all but two studies of non‐corticosteroid agents, reduced‐dose prednisolone was given with the treatment agent and the comparator was high‐dose prednisolone. In the risk of bias assessment, 11 and seven studies were at low risk of bias for sequence generation and allocation concealment, respectively. No studies were at low risk of performance bias and eight studies were at low risk of detection bias. Thirteen, 10 and six studies were at low risk of attrition bias, reporting bias and other bias, respectively.

Compared with no specific treatment, it is uncertain whether prednisolone increases the number with complete remission (1 study, 28 participants: RR 1.44, 95% CI 0.95 to 2.19), complete or partial remission (1 study, 28 participants: RR 1.38, 95% CI 0.98 to 1.95), subsequent relapse (1 study, 28 participants: RR 0.75, 95% CI 0.48 to 1.17), or reduces the adverse effects because the certainty of the evidence is very low. Compared with oral prednisolone alone, it is uncertain whether intravenous methylprednisolone and prednisolone increase the number with complete remission (2 studies, 35 participants: RR 1.76, 95% CI 0.17 to 18.32; I² = 90%), relapse (two studies, 19 participants. RR 1.18, 95% CI 0.65 to 2.15; I² = 0%) or adverse events because the certainty of the evidence is very low.

Compared with prednisolone alone, CNIs with reduced‐dose prednisolone or without prednisolone probably make little or no difference to the number achieving complete remission (8 studies; 492 participants: RR 0.99, 95% CI 0.93 to 1.05; I² = 0%), complete or partial remission (4 studies, 269 participants: RR 1.01, 95% CI 0.96 to 1.05; I² = 0%), or relapse (7 studies; 422 participants: RR 0.73, 95% CI 0.51 to 1.03; I² = 0%) (moderate certainty evidence), may reduce the risk of obesity or Cushing's Syndrome (5 studies; 388 participants: RR 0.11, 95% CI 0.02 to 0.59; I² = 45%) and the risk of acne (4 studies; 270 participants: RR 0.15, 95% CI 0.03 to 0.67; I² = 0%) (low certainty evidence); and had uncertain effects on diabetes or hyperglycaemia, hypertension, and acute kidney injury (AKI) (low certainty evidence).

Compared with prednisolone alone, EC‐MPS with reduced‐dose prednisolone probably make little or no difference to the number undergoing complete remission at 4 weeks (1 study, 114 participants: RR 1.12, 95% CI 0.84 to 1.50), and at 24 weeks probably make little or no difference to the number undergoing complete remission (2 studies, 134 participants: RR 1.12, 95% CI 0.84 to 1.38; I² = 0%) (moderate certainty evidence), complete or partial remission (2 studies 134 participants: RR 0.92, 95% CI 0.75 to 1.12; I² = 0%), relapse (2 studies, 83 participants: RR 0.50, 95% CI 0.07 to 3.74; I² = 56%) (low certainty evidence); or to the adverse events of new‐onset glucose intolerance, death, or AKI (low certainty evidence).

One study (24 participants) compared levamisole and prednisolone with prednisolone in patients with relapsing disease. The authors identified no differences in mean relapse rate or adverse effects but no standard deviations were provided.

Authors' conclusions

This updated review has identified evidence for the efficacy and adverse effects of CNIs and EC‐MPS with or without reduced‐dose prednisolone compared with prednisolone alone for the induction of remission in adults with MCD and nephrotic syndrome with some reductions in steroid‐associated adverse events. RCT data on the efficacy and adverse effects of rituximab in adults with MCD are awaited. Further, adequately powered RCTs are required to determine the relative efficacies of CNIs and EC‐MPS and to evaluate these medications in patients with relapsing or steroid‐resistant disease.

Plain language summary

Interventions for minimal change disease in adults with nephrotic syndrome

What is the issue?

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. Minimal change disease defined on kidney biopsy is the third most common primary kidney disease in adults with unexplained nephrotic syndrome (10% to 15%). The most effective treatment regimens have not been determined.

What did we do?

We identified all randomised controlled trials (RCTs), which investigated the treatment of adults with nephrotic syndrome due to minimal change disease. We searched for RCTs evaluating steroid therapy and those evaluating other agents with/without steroid therapy.

What did we find?

We found 15 studies randomising 769 participants, whose results could be evaluated. Calcineurin inhibitors (tacrolimus, cyclosporin) with/without low‐dose prednisolone were as effective as prednisolone alone in achieving remission with no differences in the numbers who were resistant or who relapsed (eight studies) but with reduced side effects of obesity and acne. Enteric‐coated mycophenolate sodium was as effective as prednisolone alone in achieving remission with no differences found in side effects. We found that it was unclear whether prednisolone compared to no treatment or intravenous methylprednisolone influences the number of participants with remission or subsequent relapse because the certainty of the evidence was very low. In a single small study, no differences in the number with remission or relapse were identified with levamisole compared with prednisolone. We did not find any completed studies evaluating rituximab but two studies are in progress.

Conclusions

We found that data included in this updated review indicate that calcineurin inhibitors and enteric‐coated mycophenolate sodium may be effective in achieving remission in adults with nephrotic syndrome due to MCD with some reduction in the side effects of high dose prednisolone therapy. Studies of these therapies in relapsing disease and in MCD resistant to prednisolone therapy are required.

Summary of findings

Background

Description of the condition

Nephrotic syndrome is a clinical condition where the glomeruli of the kidney leak protein from the blood into the urine. It is characterised by often severe generalised oedema and hypoproteinaemia and, if untreated, is associated with considerable morbidity. The causes of nephrotic syndrome are either a primary renal process or a result of injury to the kidney through systemic diseases, most commonly diabetes mellitus. Minimal change disease (MCD) is the third most common primary kidney disease in adults with idiopathic nephrotic syndrome (10% to 17%) (Gesualdo 2004; Haas 1995; Korbet 1996), after membranous nephropathy (30% to 40%) and segmental sclerosing glomerular disorders (20% to 30%) (Haas 1997). Adult‐onset MCD is associated with acute kidney injury (AKI) in 18% to 33% of patients, hypertension in 35% to 43%, microscopic haematuria in 30% to 47%, and hypercholesterolaemia in 96% (Nakayama 2002; Waldman 2007). Kidney biopsy is mandatory for a diagnosis of MCD in adults with nephrotic syndrome.

The kidney biopsy in MCD reveals no, or only minor, changes on light microscopy. The abnormality is in the fusion of the foot processes of the podocyte cell which normally forms an impermeable barrier to protein as part of the glomerular membrane that controls the urinary filtrate. While the precise pathogenesis of MCD is yet to be clarified there is increasing evidence that T lymphocytes, and probably other immune cells, are involved in the disease and may produce cytokines that alter the normal glomerular filtration membrane that prevents proteinuria (Grimbert 2003; Vivarelli 2017).

Description of the intervention

Corticosteroids have been used widely since the early 1970s for the treatment of adult‐onset MCD (Nolasco 1986). Overall 10% to 30% of adults with MCD fail to respond to corticosteroids with some found to have focal and segmental glomerulosclerosis (FSGS) on further workup (Hogan 2013; Waldman 2007). In adults, the response to corticosteroids may take much longer than in children, in whom the majority respond to corticosteroids within four weeks, with only 50% responding by four weeks and the remainder taking up to 16 weeks to respond (Hogan 2013). Spontaneous remission is infrequent, although prior to the widespread use of corticosteroids a spontaneous rate of remission was reported in over half of patients in the first two years after diagnosis (Black 1970). The development of MCD in those older than 40 years may be characterised by increased rates of kidney impairment and hypertension, although these features may simply reflect age‐related changes (Tse 2003). Relapse of the nephrotic syndrome after remission may occur in 70% to 80% of adults with MCD (Hogan 2013; Waldman 2007) with the average time to relapse being about 22 weeks (Waldman 2007). Frequent relapses occur in 10% to 30% of patients of whom 15% to 30% become steroid‐dependent (Korbet 2019). Older patients may have different remission rates to corticosteroids (Korbet 1996; Nakayama 2002).

The use of other immunosuppressive interventions in adult MCD is largely based on the responses to treatment seen in children with steroid‐sensitive nephrotic syndrome. Remission rates with cyclophosphamide (CPA) given orally or intravenously (IV) are reported in 50% to 80% of patients (Hogan 2013; Nolasco 1986; Waldman 2007) though up to 50% will relapse (Hogan 2013). CNIs (cyclosporin and tacrolimus) are often used with a reduced dose of prednisolone to treat the initial episode of MCD and relapsing disease particularly in adult patients at risk of serious adverse events with high dose prednisolone (Hogan 2013; Li 2017b) with similar remission and relapse rates to those seen with prednisolone alone. More recently mycophenolic acid analogues (mycophenolate mofetil (MMF) or mycophenolate sodium (MPS)) and the anti CD20 monoclonal antibody, rituximab, have been used in adults with MCD with beneficial effects (MSN 2018; Munyentwali 2013). Adverse effects from immunosuppression depend on the agent used and include infection, malignancy, peptic ulceration, diabetes mellitus, infertility, kidney failure, bone marrow suppression, hypertrichosis and alopecia.

Supportive therapies include angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin‐receptor blockers (ARB) to reduce proteinuria and hydroxymethylglutaryl coenzyme A (HMG Co‐A) reductase inhibitors (statins) to reduce cholesterol are now considered standard adjuvant therapies for adults with MCD.

How the intervention might work

The immunological mechanisms causing MCD are not well understood. However, there is evidence to suggest that both B cell and T cell dysfunction exist in MCD (Vivarelli 2017) leading to increased permeability of the glomerular wall to albumin with hypoalbuminaemia and proteinuria. Clinical observations in children and in adults demonstrating the response of nephrotic syndrome to corticosteroids and other immunosuppressive agents provide supporting evidence for the dysfunction. Each immunosuppressive agent used in nephrotic syndrome has a different mechanism of action. Prednisolone binds to glucocorticoid receptors in the cell cytoplasm. The activated complex exerts its immunosuppressive effects by increased expression of anti‐inflammatory genes and decreased expression of pro‐inflammatory genes (Schijvens 2019). Cyclophosphamide (CPA) binds to DNA and its cytotoxic effect is due to cross‐linking of strands of DNA and RNA and to inhibition of protein synthesis. CNIs block the activation of T cells. Mycophenolic acid inhibits de novo purine synthesis limiting T and B cell proliferation. Rituximab is a chimeric monoclonal antibody that binds to the CD20 antigen on B cells leading to B cell depletion. Levamisole is a synthetic imidazothiazole derivative with immune‐modulatory properties (Mühlig 2019).

Why it is important to do this review

The treatment of adult‐onset MCD has developed largely based on randomised controlled trials (RCTs) in children. The initial duration of prednisolone therapy for 16 weeks was based on the observation that adults often take much longer to achieve remission compared with children. Similarly, the use of non‐corticosteroid immunosuppressive agents has until recently been based on observational studies in MCD and on RCTs using these agents in other autoimmune diseases in adults. This systematic review is an update of a review published in 2008 when only three RCTs evaluating prednisolone were identified. Since the original publication, there has been increasing use of non‐corticosteroid agents including CNIs, mycophenolic acid analogues and rituximab in adult MCD. Therefore we aimed to identify new RCTs evaluating these agents in adult patients with MCD and to assess them for efficacy and adverse effects.

Objectives

To evaluate the benefits and harms of different agents, including both immunosuppressive and non‐immunosuppressive agents, in adults with MCD causing the nephrotic syndrome.
To evaluate the efficacy of interventions on 'time‐to‐remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome.

Methods

Criteria for considering studies for this review

Types of studies

All 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) looking at any intervention for MCD in adults with the nephrotic syndrome were included. Immunosuppressive agents included corticosteroids (prednisolone, methylprednisolone), alkylating agents (CPA, chlorambucil), azathioprine, CNIs (cyclosporin, tacrolimus), target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus), mycophenolic acid analogues (MMF, MPS) and the immunomodulator levamisole. Non‐immunosuppressive agents included NSAIDs, ACEi, ARBs, heparinoids, parenteral albumin, and statins. The first periods of cross‐over RCTs were to be included.

Types of participants

Inclusion criteria

Adults (> 18 years) with nephrotic syndrome and biopsy‐proven MCD were included. Nephrotic syndrome was defined as proteinuria > 3.0 g/24 hour, oedema, and hypercholesterolaemia.

Exclusion criteria

Studies enrolling paediatric patients were excluded as these are the subject of other reviews by Cochrane Kidney and Transplant (Hahn 2020; Larkins 2020; Liu 2019). Studies enrolling patients who had any type of segmental sclerosing abnormality on kidney biopsy (all variants of FSGS) were excluded. Any RCT enrolling patients with secondary MCD (e.g. related to drug therapy) were excluded.

Types of interventions

All immunosuppressive agents were considered and included the following:

Corticosteroid agent versus placebo or no treatment
Different doses and/or durations and routes of administration of corticosteroid treatments
Non‐corticosteroid immunosuppressive agent (with or without concomitant corticosteroid treatment) versus corticosteroid agent alone. These non‐corticosteroid agents included azathioprine, CPA, chlorambucil, CNIs (cyclosporin, tacrolimus), TOR‐I inhibitors (sirolimus, everolimus), levamisole, mycophenolic acid analogues (MMF, MPS) and rituximab
Comparisons between two different non‐corticosteroid agents (with or without concomitant corticosteroid agent)
Different doses, durations, and routes of the same non‐corticosteroid immunosuppressive agent (with or without concomitant use of corticosteroid agent).

All studies where participants were randomised to a non‐immunosuppressive agent were to be included if identified. These included:

Non‐immunosuppressive agent versus placebo or no treatment
Immunosuppressive agent versus non‐immunosuppressive agent
Comparisons between two different non‐immunosuppressive agents.

Types of outcome measures

Primary outcomes

The number of patients who achieved complete remission during and following therapy (i.e. oedema free and proteinuria < 1+ (on dipstick), or urinary protein:creatinine ratio (UPCR) < 0.03 g/mmol or complete remission as defined by the investigators).

Secondary outcomes

Number of patients who achieved partial remission with reduction in proteinuria (i.e. proteinuria < 2+ on dipstick, UPCR < 0.3 g/mmol, protein excretion < 3 g/d or partial remission as defined by the triallists)
Time to remission (days) of nephrotic syndrome
Reduced kidney function (reduced estimated glomerular filtration rate (eGFR))
Kidney failure (GFR ≤ 15 mL/min or requiring kidney replacement therapy)
One or more episodes of thrombosis
Death (any cause)
Fatal and non‐fatal cardiovascular events (myocardial infarction, stroke, revascularization)
Adverse events including major infection requiring parenteral antibiotics or hospitalisation, infection (any cause), hypertension, malignancy, kidney failure (as defined by the triallists or a rise in the serum creatinine (SCr) > 0.03 mmol/L or a fall in eGFR > 25%), diabetes mellitus/impaired glucose tolerance, gonadal failure (sustained amenorrhoea or infertility), bone toxicity (avascular necrosis or fracture), bone marrow toxicity, bladder toxicity (haemorrhagic cystitis), hypertrichosis, gingival hyperplasia, alopecia, peptic ulceration.

Analyses of the following continuous variables were planned but most studies did not provide the required information for these outcomes:

End of treatment mean SCr (mmol/L)
End of treatment mean protein excretion rate (g/24 hours) or UPCR (g/mmol)
End of treatment mean serum albumin (g/L)
End of treatment mean serum total cholesterol (mmol/L)
End of treatment mean serum low‐density lipoprotein (LDL), cholesterol/high‐density lipoprotein (HDL), cholesterol/triglycerides (all mmol/L) and HDL:LDL cholesterol ratio
Protein excretion rate at 6, 12 and 24 months (g/24 hours) after treatment
Duration of complete remission or partial remission (months).

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, have been searched.

Data collection and analysis

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 might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if 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 four authors using standard data extraction forms. Studies reported in non‐English language journals were to be translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was included in the analyses. Where relevant outcomes are only published in earlier versions these data were used. Any discrepancy between published versions was highlighted.

Assessment of risk of bias in included studies

The following items were independently assessed by four authors using the risk of bias assessment tool (Higgins 2020) (see Appendix 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 risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. death, remission or no remission, relapse, adverse effects ) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (time to remission, time to relapse), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales had been used.

Unit of analysis issues

We did not identify any cross‐over studies. If we had done, then we would have used the data from the first part of the study before the cross‐over.

Dealing with missing data

Any further information required from the original author was requested by written correspondence (e.g. emailing and/or writing to corresponding author/s) and any relevant information obtained in this manner was included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat (ITT), as‐treated and per‐protocol population was carefully performed. Attrition rates, for example, drop‐outs, losses to follow‐up and withdrawals were investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) were critically appraised (Higgins 2020). 

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 2020).

Assessment of reporting biases

Because of limited data, funnel plots could not be used to assess for the potential existence of small study bias (Higgins 2020).

Data synthesis

Data were pooled using the random‐effects model but the fixed‐effect model was also used to ensure the robustness of the model chosen and susceptibility to outliers. 

Subgroup analysis and investigation of heterogeneity

We did not identify sufficient studies to allow any subgroup analysis to explore possible sources of heterogeneity related to participants (age, duration of disease, initial episode compared with relapse), interventions (corticosteroids, non‐corticosteroid agents) or study quality. Any heterogeneity identified could be related to whether the participants were treated in their initial episode or after relapse or to the regimen for administering the test intervention in different studies (for example different types and durations of calcineurin inhibitors).

Sensitivity analysis

We were not able to perform sensitivity analyses according to the factors below because of the limited number of studies available:

Repeating the analysis excluding unpublished studies
Repeating the analysis taking account of the risk of bias
Repeating the analysis excluding any very long duration or large studies to establish how much they dominated the results
Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), or country.

Summary of findings and assessment of the certainty of the evidence

We have 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 (Schünemann 2020a). The 'Summary of findings' tables also includes 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 to 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 the within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, the precision of effect estimates and risk of publication bias (Schünemann 2020b). We presented the following outcomes in the 'Summary of findings' tables.

Complete remission
Complete or partial remission
Relapse during follow‐up
Adverse effects including death, AKI, new‐onset diabetes mellitus, thromboses, hypertension, obesity or Cushing's Syndrome, and cosmetic effects.

Results

Description of studies

Results of the search

For the 2008 review (Figure 1), 3845 reports were identified from Cochrane Kidney and Transplant's specialised register, CENTRAL, MEDLINE and EMBASE and CENTRAL, 3780 reports were excluded after screening titles and abstracts, and 65 reports underwent full‐text review. Three studies (Coggins 1986; Imbasciati 1985; Yeung 1983) were included, and 55 studies (62 reports) were excluded.

Literature searches to 21 July 2021 identified 29 new reports. Of these, 11 studies (Eguchi 2010; Inoue 2010; Kirubakaran 1984; Li 2017b; Ma 2019; Medjeral‐Thomas 2020; Miao 2006; MSN 2018; Patil 2019; Shirai 2018; T‐OPTIMUM 2021) were included, two new studies were excluded (Li 2008a; Simon 1989), and we identified five ongoing studies (ADAPTinMCN 2018; CTRI/2015/12/006439; NCT03298698; Trachtman 2018; TURING 2019). We also identified two new reports of two existing excluded studies. A study excluded in 2008, was re‐evaluated and included in this update (Black 1970). We have deleted 53 previously excluded studies, not randomised (22), studies performed in children (11), and the population did not have MCD (20), as per the Cochrane Handbook (Higgins 2020).

This 2021 update includes 15 included studies (769 participants), five ongoing studies, and four excluded studies (Figure 1).

Included studies

Fifteen studies were included.

Four studies (Black 1970; Coggins 1986; Imbasciati 1985; Yeung 1983) evaluated prednisolone using various regimens (99 participants; 68 meta‐analysed).
- Two studies (Black 1970; Coggins 1986) compared prednisone with no specific treatment.
- Two studies (Imbasciati 1985; Yeung 1983) compared IV and oral steroids versus oral steroids alone.
One study (Kirubakaran 1984) compared levamisole with prednisolone (24 participants).
Two studies (Ma 2019; MSN 2018) compared MPS and reduced dose prednisolone with prednisolone alone (134 participants; 134 meta‐analysed).
Eight studies (Eguchi 2010; Inoue 2010; Li 2017b; Medjeral‐Thomas 2020; Miao 2006; Patil 2019; Shirai 2018; T‐OPTIMUM 2021) compared calcineurin inhibitors (tacrolimus or cyclosporin) with reduced prednisolone or without prednisolone with prednisolone alone (starting dose usually 1 mg/kg/day) (492 participants, 492 were meta‐analysed).
- Three studies (Eguchi 2010; Inoue 2010; Shirai 2018) administered cyclosporin with reduced dose oral prednisolone compared with oral prednisolone alone for 6‐12 months.
- Four studies (Miao 2006; Medjeral‐Thomas 2020; Patil 2019; T‐OPTIMUM 2021) compared tacrolimus with (Miao 2006; T‐OPTIMUM 2021) or without (Medjeral‐Thomas 2020; Patil 2019) oral prednisolone with oral prednisolone for 6 to 12 months.
- One study (Li 2017b) compared tacrolimus with oral prednisolone for 12 months and both groups received IV methylprednisolone for 10 days at the beginning of treatment.

Ongoing studies

Five ongoing studies were identified.

CTRI/2015/12/006439 : different tapering doses of prednisolone in adults with MCD
ADAPTinMCN 2018: alfacalcidol and reduced dose prednisolone compared with high dose prednisolone in adults with MCD
NCT03298698: rituximab compared with prednisolone in adults with MCD
TURING 2019: rituximab compared with prednisolone in adults with MCD or FSGS
Trachtman 2018: abatacept compared with placebo in adults with MCD or FSGS.

Excluded studies

Four studies were excluded.

Edefonti 1988: data for adults and children could not be separated
Li 2008a: hepatitis B‐associated MCD
Ponticelli 1993a: data for adults with MCD or FSGS could not be separated
Simon 1989: unclear whether the study was an RCT.

Risk of bias in included studies

Risk of bias items are shown in Figure 2; Figure 3.

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

Eleven studies (Black 1970; Eguchi 2010; Imbasciati 1985; Li 2017b; Ma 2019; Medjeral‐Thomas 2020; Miao 2006; MSN 2018; Patil 2019; Shirai 2018; T‐OPTIMUM 2021) were at low risk of bias for sequence generation. Four studies were at unclear risk of bias for sequence generation.

Allocation concealment

Seven studies (Black 1970; Eguchi 2010; Ma 2019; Medjeral‐Thomas 2020; MSN 2018; Patil 2019; T‐OPTIMUM 2021) were at low risk of bias for allocation concealment while eight studies were at unclear risk.

Blinding

Performance bias

All studies were at high risk of performance bias.

Detection bias

Eight studies (Li 2017b; Ma 2019; Medjeral‐Thomas 2020; Miao 2006; MSN 2018; Patil 2019; Shirai 2018; T‐OPTIMUM 2021) were at low risk of detection bias and three studies (Eguchi 2010; Imbasciati 1985; Yeung 1983) were at high risk of detection bias. Detection bias was unclear in four studies (Black 1970; Coggins 1986; Inoue 2010; Kirubakaran 1984).

Incomplete outcome data

Attrition bias was at low risk of bias in 13 studies and at high risk of bias in two studies (Black 1970; Li 2017b)

Selective reporting

Reporting bias was at low risk of bias in 10 studies, at high risk of bias in four studies (Black 1970; Eguchi 2010; Kirubakaran 1984; Yeung 1983) and at unclear risk of bias in one study (Shirai 2018).

Other potential sources of bias

Six studies were at low risk of other bias (Li 2017b; Ma 2019; Medjeral‐Thomas 2020; Miao 2006; MSN 2018; Patil 2019). One study was at high risk of bias (T‐OPTIMUM 2021). Eight studies were at unclear risk of other bias.

Effects of interventions

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

Summary of findings 1. Steroids versus no specific treatment for minimal change disease in adults with nephrotic syndrome.

Steroid verus no specific treatment for minimal change disease in adults with nephrotic syndrome
Patient or population: minimal change disease in adults with nephrotic syndrome Setting: University hospitals Intervention: steroid Comparison: no specific treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with no specific treatment	Risk with steroids	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Complete remission Time frame: to 77 months	643 per 1,000	926 per 1,000 (611 to 1,000)	RR 1.44 (0.95 to 2.19)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Complete or partial remission Time frame: to 77 months	714 per 1,000	986 per 1,000 (700 to 1,000)	RR 1.38 (0.98 to 1.95)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Relapse during follow‐up Time frame: to 77 months	857 per 1,000	643 per 1,000 (411 to 1,000)	RR 0.75 (0.48 to 1.17)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Adverse events: avascular necrosis	No events	1/14**	RR 3.00 (0.13 to 67.91)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Adverse events: doubling serum creatinine	286 per 1,000	31 per 1,000 (3 to 540)	RR 0.11 (0.01 to 1.89)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Adverse events: kidney failure	71 per 1,000	24 per 1,000 (1 to 539)	RR 0.33 (0.01 to 7.55)	28 (1)	⊕⊝⊝⊝ VERY LOW ^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 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  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

IV ± oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome
Patient or population: minimal change disease in adults with nephrotic syndrome Setting: university hospitals Intervention: IV ± oral steroids Comparison: oral steroids alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with oral steroids alone	Risk with IV ± oral steroids	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Complete remission Time frame: 2 to 28 months	667 per 1,000	1000 per 1,000 (113 to 1,000)	RR 1.76 (0.17 to 18.32)	35 (2)	⊕⊝⊝⊝ VERY LOW ^{1 2 3}
Complete or partial remission	Not reported	Not reported	‐‐	‐‐	‐‐
Relapse during follow‐up Time frame: 12 months	636 per 1,000	751 per 1,000 (414 to 1,000)	RR 1.18 (0.65 to 2.15)	19 (1)	⊕⊝⊝⊝ VERY LOW ^{1 3}
Adverse events: thromboses	182 per 1,000	91 per 1,000 (9 to 864)	RR 0.50 (0.05 to 4.75)	22 (1)	⊕⊝⊝⊝ VERY LOW ^{1 3}
Adverse events: gastrointestinal bleeding	125 per 1,000	16 per 1,000 (19 to 50)	RR 0.13 (0.40 to 0.15)	18 (1)	⊕⊝⊝⊝ VERY LOW ^{1 3}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  IV: Intravenous; 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 inhibitors ± oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome
Patient or population: minimal change disease in adults with nephrotic syndrome Setting: hospital setting Intervention: CNI ± oral steroids Comparison: oral steroids alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with oral steroids alone	Risk with CNI ± oral steroids	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Complete remission Time frame: 2 to 6 months	868 per 1,000	860 per 1,000 (808 to 912)	RR 0.99 (0.93 to 1.05)	492 (8)	⊕⊕⊕⊝ MODERATE ¹
Complete or partial remission time frame: 3 to 6 months	908 per 1,000	917 per 1,000 (872 to 954)	RR 1.01 (0.96 to 1.05)	269 (4)	⊕⊕⊕⊝ MODERATE ¹
Relapse Time frame: 6 to 12 months	263 per 1,000	192 per 1,000 (134 to 271)	RR 0.73 (0.51 to 1.03)	422 (7)	⊕⊕⊕⊝ MODERATE ¹
Adverse effects: diabetes or hyperglycaemia	59 per 1,000	28 per 1,000 (11 to 74)	RR 0.48 (0.19 to 1.25)	450 (7)	⊕⊕⊝⊝ LOW ^{1 2}
Adverse effects: obesity or Cushing's Syndrome	289 per 1,000	32 per 1,000 (9 to 123)	RR 0.11 (0.02 to 0.59)	388 (5)	⊕⊕⊝⊝ LOW ^{1 2}
Adverse effects: hypertension	38 per 1,000	33 per 1,000 (9 to 123)	RR 0.86 (0.23 to 3.20)	219 (3)	⊕⊕⊝⊝ LOW ^{1 2}
Adverse events: acute kidney injury	27 per 1,000	48 per 1,000 (9 to 243)	RR 1.78 (0.35 to 8.99)	270 (4)	⊕⊕⊝⊝ LOW ^{1 2}
Adverse effects: acne	126 per 1,000	19 per 1,000 (4 to 84)	RR 0.15 (0.03 to 0.67)	270 (4)	⊕⊕⊝⊝ LOW ^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CNI: Calcineurin inhibitors; 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

Mycophenolate sodium + oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome
Patient or population: minimal change disease in adults with nephrotic syndrome Setting: University hospitals Intervention: MPS + reduced dose oral steroids Comparison: oral steroids alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with oral steroid	Risk with MPS + oral steroid	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Complete remission Time frame: 4 weeks	579 per 1,000	648 per 1,000 (486 to 868)	RR 1.12 (0.84 to 1.50)	114 (1)	⊕⊕⊕⊝ MODERATE ¹
Complete remission Time frame: 24 weeks to end of treatment	627 per 1,000	677 per 1,000 (527 to 865)	RR 1.08 (0.84 to 1.38)	134 (2)	⊕⊕⊕⊝ MODERATE ²
Complete or partial remission Time frame: 24 weeks to end of treatment	746 per 1,000	687 per 1,000 (560 to 836)	RR 0.92 (0.75 to 1.12)	134 (2)	⊕⊕⊕⊝ MODERATE ²
Relapse Time frame: 24 weeks	200 per 1,000	86 per 1,000 (16 to 450)	RR 0.43 (0.08 to 2.25)	80 (2)	⊕⊕⊝⊝ LOW ^{3 4}
Adverse events: death	52 per 1,000	35 per 1,000 (6 to 199)	RR 0.67 (0.12 to 3.84)	116 (1)	⊕⊕⊝⊝ LOW ⁵
Adverse events: acute kidney injury	34 per 1,000	17 per 1,000 (2 to 185)	RR 0.50 (0.05 to 5.36)	116 (1)	⊕⊕⊝⊝ LOW ⁵
Adverse events: new‐onset glucose intolerance	29 per 1,000	6 per 1,000 (0 to 120)	RR 0.20 (0.01 to 4.08)	136 (2)	⊕⊕⊝⊝ LOW ⁶
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  MPS: Mycophenolate sodium; 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

Date	Event	Description
28 December 2021	New citation required and conclusions have changed	New interventions identified
28 December 2021	New search has been performed	12 new studies included

Date	Event	Description
14 May 2019	Amended	Search strategies updated
13 August 2009	Amended	Contact details updated
14 May 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	MeSH descriptor: [Nephrosis, Lipoid] this term only MeSH descriptor: [Nephrotic Syndrome] this term only "nephrotic syndrome" "minimal change disease" "minimal change glomerulonephritis" "nil disease" "lipoid nephrosis" "idiopathic nephrotic syndrome" {or #1‐#8}
MEDLINE (OVID)	Nephrosis Lipoid/ Nephrotic Syndrome/ nephrotic syndrome.tw. minimal change disease.tw. minimal change glomerulonephritis.tw. minimal change nephro$.tw. nil disease.tw. lipoid nephrosis.tw. 0r/1‐8
EMBASE (OVID)	minimal change glomerulonephritis/ Lipoid Nephrosis/ Nephrotic Syndrome/ nephrotic syndrome.tw. minimal change disease.tw. minimal change glomerulonephritis.tw. minimal change nephr$.tw. nil disease.tw. lipoid nephrosis.tw. or/1‐9

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; minimisation (minimisation 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 standardised 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. sub‐scales) 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	Statistical method	Effect size
1.1 Remission	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1.1 Complete remission	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1.2 Complete or partial remission	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.2 Relapse during follow‐up	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3 Adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3.1 Avascular necrosis	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3.2 Doubling serum creatinine	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3.3 Kidney failure	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3.4 Psychosis	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Complete remission	2	35	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.17, 18.32]
2.2 Relapse during follow‐up	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.3 Adverse effects	2		Risk Difference (M‐H, Random, 95% CI)	Totals not selected
2.3.1 Gastrointestinal bleed	1		Risk Difference (M‐H, Random, 95% CI)	Totals not selected
2.3.2 Thromboses	1		Risk Difference (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Remission	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1.1 Complete remission (2 to 6 months)	8	492	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.93, 1.05]
3.1.2 Complete or partial remission (1 to 6 months)	4	269	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.96, 1.05]
3.2 Complete remission stratified for steroid use with CNI	8	492	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.93, 1.05]
3.2.1 CNI + steroids vs steroids alone	6	392	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.94, 1.06]
3.2.2 CNI vs steroids alone	2	100	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.61, 1.00]
3.3 Relapse	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.3.1 Relapse (6 to 12 months)	7	422	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.51, 1.03]
3.3.2 Relapse (12 to 30 months)	4	218	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.72, 1.13]
3.3.3 Frequent relapses or drug dependence	1	106	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.19, 1.14]
3.4 Time to complete remission	5	220	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.82, 0.47]
3.5 Adverse effects	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.5.1 Diabetes or hyperglycaemia	7	450	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.19, 1.25]
3.5.2 Obesity or Cushing's	5	388	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.02, 0.59]
3.5.3 Hypertension	3	219	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.23, 3.20]
3.5.4 Acute kidney injury	3	303	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.35, 8.99]
3.5.5 Acne	4	270	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.03, 0.67]
3.5.6 Infections	4	355	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.23, 2.28]

*Study characteristics*
Methods	Study design: parallel open‐label RCT Study duration/time frame: September 2011 to May 2013 Follow‐up period: 36 weeks (therapy) and 64 weeks (after therapy)
Participants	Country: China Setting: multi‐centre (8 sites) Inclusion criteria: Biopsy‐proven idiopathic minimal change nephropathy, first episode, 18 to 65 years; new‐onset nephrotic syndrome; initial SCr < 133 μmol/L and urine volume > 600 mL/day (or 1000 mL/day after diuretics) Numbers (randomised/analysed; ITT analysis): treatment group (63/63), control group (56/56) Numbers (randomised/analysed; per‐protocol analysis for primary outcome): treatment group (63/56); control group (56/53) Loss to follow‐up: treatment group (5/63); control group (5/56) Mean age ± SD (years): treatment group (29.9 ± 12); control group (28.6 ± 10) Sex (M/F): treatment group (37/26); control group (30/26) Mean kidney function ± SD (eGFR, mL/min/1.73 m²): treatment group (122.8 ± 31.9); control group (120.3 ± 34.7) Mean baseline proteinuria ± SD (g/day): treatment group (7.1 ± 4.1); control group (7.8 ± 3.8) Exclusion criteria: secondary MCD; AKI; hepatitis B or C infection; DM; history of pancreatitis or GI ulcer; history of congenital or acquired immunodeficiency; previous treatment with corticosteroids or other immunosuppressants
Interventions	Treatment group Methylprednisolone (IV): 0.8 mg/kg/day for 10 days TAC (oral, from day 8): 0.05 mg/kg/day in 2 doses adjusted for target trough level 4 to 8 ng/mL for 16 to 20 weeks, then 2 to 5 ng/mL for approximately 18 weeks Duration of therapy: 4.5 months Control group Methylpredisolone (IV): 0.8 mg/kg/day for 10 days Prednisolone (oral, from day 11): 1 mg/kg/day for 6 to 8 weeks; then reduced by 5 mg every week to 30 mg on alternate days and maintained for 8 weeks followed by tapering of the dose over approximately 12 weeks Duration of therapy: 4.5 months Co‐interventions ACEi, ARB, other antihypertensive medication and statins administered as required
Outcomes	Primary outcomes Complete remission Partial remission Secondary outcomes Relapses Time to remission Time to relapse Changes in SCr and eGFR AKI Metabolic disorders Adverse events
Notes	Primary outcomes were analysed only by per‐protocol analysis (only the patients who completed 12 weeks of treatment) Funding source: National Nature Science Foundation of China
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The minimization method was applied using a computer generated sequence.”
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes confirmed by laboratory methods
Incomplete outcome data (attrition bias) All outcomes	High risk	Efficacy only reported for patients who completed 12 weeks of treatment (per‐protocol analysis)
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	Financial support reported (National Nature Science Foundation of China)

*Study characteristics*
Methods	Study design: parallel, open‐label RCT Study duration/time frame: not reported Follow‐up period: 24 weeks
Participants	Country: Hong Kong and Macao (China) Setting: multicentre (2 sites) Inclusion criteria: 18 to 65 years; proteinuria > 3.5 g/day; idiopathic MCD; initial episode previously untreated Numbers randomised/analysed: treatment group (10/10); control group (10/10) Mean age ± SD (years): treatment group (31.9 ± 13.5); control group (56.9 ± 17.3) Sex (M/F): treatment group (5/5); control group (5/5) Mean kidney function ± SD (eGFR, mL/min): treatment group (118 ± 30); control group (72 ± 30) Mean baseline proteinuria ± SD (g/day): treatment group (6.1 ± 2.9); control group (6.1 ± 3.1) Exclusion criteria: GN secondary to other conditions; previous treatment for GN; concurrent treatment with steroids, NSAIDs or immunosuppressive agents; pregnant or intending to conceive or of child‐bearing age unwilling to practice effective contraception; unable to give informed consent
Interventions	Treatment group EC‐MPS: 720 mg twice/day (540 mg twice daily if BW < 60 kg) for 24 weeks and then stopped Prednisolone: 0.25 mg/kg/day for 8 weeks then 0.15 mg/kg/day for 8 weeks then 0.1 mg/kg/day for 8 weeks then stopped Total duration: 24 weeks Control group Prednisolone: 1 mg/kg/day to be tapered over a period of 24 weeks at the discretion of the attending physician Co‐interventions ACEi/ARB, other antihypertensive agents, statins
Outcomes	Primary outcome Complete remission at 24 weeks Secondary outcomes Partial remission Adverse effects: cushingoid facies, striae, acne, weight gain, GI disturbance, cytopenia, infection GFR and 24‐hour urine protein excretion at the end of the study
Notes	Information on random sequence generation and allocation concealment requested and received from Professor Tang, the senior author Funding source: supported by several private donors and an Endowment Fund established for the ‘Yu Professorship in Nephrology’ at the University of Hong Kong awarded to senior author
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Random sequence generated by computer and kept by research nurse who allocated participants according to the sequence after informed consent was obtained"
Allocation concealment (selection bias)	Low risk	Patients allocated to treatment groups by research nurse without input from physician investigators
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary outcome was defined by laboratory outcome of 24‐hour urine protein excretion
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted for
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	Supported by several private donors and an Endowment Fund established for the ‘Yu Professorship in Nephrology’ at the University of Hong Kong awarded to senior author

*Study characteristics*
Methods	Study design: parallel, open‐label RCT Study duration/time frame: February 2002 to June 2005 Follow‐up period: 6 months
Participants	Country: China Setting: single centre Inclusion criteria: diagnosis of non‐IgA primary nephrotic syndrome with slight mesangial proliferation; no previous therapy with other immunosuppressives or NSAIDs prior to inclusion in the study; initial blood glucose level, kidney and liver function normal Number (randomised/analysed): treatment group (30/30); control group (30/30) Mean age ± SD (years): treatment group (35.8 ± 10.6); control group (37.1 ± 11.7) Sex (M/F): treatment group (19/11); control group (17/13) Mean kidney function ± SD (CrCl, mL/min): treatment group (97 ± 6); control group (105 ± 13) Mean baseline proteinuria ± SD (g/day): treatment group (13.71 ± 6.14); control group (11.95 ± 5.97) Exclusion criteria: pregnancy; known allergy to CNIs; active infectious diseases
Interventions	Treatment group Prednisolone (oral): 30 mg/day for 6 weeks; then tapered by 5 mg/week until 10 mg/day and maintained for 6 months TAC (oral): 2 mg/day in 2 divided doses Control group Prednisolone (oral): 1 mg/kg/day (maximum 60 mg) for 8 to 12 weeks; then tapered by 5 mg/week until 10 mg/day and maintained Co‐interventions Prohibited use of NSAIDs, ACEi, ARB
Outcomes	Complete remission Partial remission Adverse events BMI Proteinuria
Notes	Funding source: Tengze Foundation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The randomization was performed through a preprinted randomization table”
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes determined by laboratory tests and/or objective clinical measurements
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients completed planned treatment duration. No loss to follow‐up
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	Non‐industry funding by Tengze Foundation

Study name	Treatment of primary minimal change nephropathy: a randomized open‐labeled non‐inferiority study on prednisolone and vitamin D
Methods	Open‐label, parallel RCT
Participants	Nephrotic syndrome and biopsy‐proven MCD (if earlier MCD then no relapse in 5 years, and earlier only treated with prednisolone) Estimated number of participants: 96
Interventions	Treatment group Alfacalcidol: 0.5 µg/day Prednisolone: 0.5 mg/kg/day Control group Prednisolone: 1 mg/kg/day
Outcomes	Primary Remission Secondary Relapse Side effects. Side effects to prednisolone will be assessed using questionnaires by both patients and doctors, including SF36 and Cushing QoL, Glucocorticoid Toxicity Index
Starting date	May 1, 2018
Contact information	Tilde Kristensen, MD: tilde.kristensen@rm.dk Per Ivarsen: perivars@rm.dk
Notes	Estimated completion date: December 31, 2022. NCT03210688

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Complete remission	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1.1 Four weeks	1	114	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.84, 1.50]
4.1.2 Eight weeks	1	114	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.82, 1.43]
4.1.3 24 weeks ‐ end of treatment	2	134	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.84, 1.38]
4.2 Complete or partial remission	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.2.1 Four weeks	1	114	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.71, 1.20]
4.2.2 Eight weeks	1	114	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.75, 1.16]
4.2.3 24 weeks ‐ end of treatment	2	134	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.12]
4.3 Relapse by 24 weeks	2	80	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.08, 2.25]
4.4 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.4.1 Death	1	116	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.84]
4.4.2 Acute kidney injury	1	116	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.05, 5.36]
4.4.3 New‐onset glucose intolerance	2	136	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.08]
4.4.4 Acute pulmonary embolism	1	116	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 72.15]
4.4.5 Bone fracture	1	116	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.08]
4.4.6 Infections	1	116	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.45, 5.04]

*Study characteristics*
Methods	Study design: parallel RCT Study duration/time frame: recruitment took 3.5 years; dates not reported Average duration of follow‐up: at least 2 years
Participants	Country: UK Setting: multicentre (tertiary centres, number not reported) Inclusion criteria: biopsy‐proven idiopathic minimal change nephrotic syndrome < 1 year with no previous treatment; proteinuria persisting for at least 4 weeks before study entry Number (randomised/analysed): 31 patients with MCD entered. Number in each group not reported Mean age ± SD (years): not reported Sex (M/F): 17/14 Kidney function: not reported Baseline proteinuria: treatment group (9.8 g/day); control group (9.8 g/day) Exclusion criteria: steroids for nephrotic syndrome or other conditions in the past year
Interventions	Treatment group Prednisolone: 20 to 30 mg/day for at least 6 months. Mean dose tapered after 6 months Control group No specific treatment Co‐interventions Nor reported
Outcomes	% with proteinuria > 1 g/day Death Kidney function
Notes	Study also included patients with membranous nephropathy and mesangiocapillary glomerulonephritis and results could not be separated between different pathologies so data could not be included in meta‐analyses Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Allocation was carried out centrally and was randomized both within the three main histological categories and within the various hospitals”
Allocation concealment (selection bias)	Low risk	Quote: “Allocation was carried out centrally and was randomized both within the three main histological categories and within the various hospitals”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided on how outcome was assessed though presumed to be 24‐hour urine protein excretion
Incomplete outcome data (attrition bias) All outcomes	High risk	Numbers in treatment and control groups not reported so data could not be included in meta‐analyses
Selective reporting (reporting bias)	High risk	Incomplete reporting of important outcomes including adverse effects
Other bias	Unclear risk	Insufficient information to permit judgement

*Study characteristics*
Methods	Study design: parallel, placebo‐controlled RCT Study duration/time frame: not reported Average duration of follow‐up before "stop points": treatment group (60 months); control group (50 months) Average total duration of follow‐up: treatment group (89 months); control group (85 months)
Participants	Country: USA Setting: multicentre (tertiary centres ‐ number not reported) Inclusion criteria: idiopathic minimal change nephrotic syndrome; not reported if first episode or relapse (disease duration 2 months) Number (randomised/analysed): treatment group (14/14); control group (14/14) Mean age (years): treatment group (29); control group (32) Sex (M/F): not reported Kidney function: not reported Baseline proteinuria: treatment group (9.8 g/day); control group (9.8 g/day) Exclusion criteria: not reported
Interventions	Treatment group Prednisolone (oral): 125 mg given in alternate‐day doses for 2 months Relapses were re‐treated Control group No treatment Co‐intervention Not reported If patients reached "stop points" (doubling of admission SCr, severe steroid toxicity, "other bad outcomes") they were withdrawn from the study but follow‐up continued
Outcomes	Complete remission prior to "Stop Points" Partial remission Time to remission (months) Doubling of SCr ESKD Steroid‐related toxicity (avascular necrosis)
Notes	Exclusions post‐randomisation but pre‐intervention: not reported Additional data requested from authors: Method of randomisation, allocation concealment Completeness of follow‐up: unclear Definitions of outcomes not provided Part of United States‐based Collaborative Study of Adult Glomerular Disease Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation method not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of participants and personnel not reported so likely to be open‐label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided on how outcomes were measured
Incomplete outcome data (attrition bias) All outcomes	Low risk	All enrolled patients were analysed
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Study	Reason for exclusion
Edefonti 1988	Wrong population: multicentre RCT of 73 patients (adults and children) comparing CPA with CSA in steroid‐dependent or frequently relapsing idiopathic nephrotic syndrome. Included some participants with a kidney biopsy showing FSGS and data could not be separated from those with MCD
Li 2008a	Wrong population: RCT involving patients with hepatitis B‐associated MCD
Ponticelli 1993a	Wrong population: RCT of CSA in steroid‐resistant idiopathic nephrotic syndrome. Included people with either MCD or FSGS and data could not be separated
Simon 1989	Wrong study design: unclear whether this study is an RCT. The authors report that they compared two groups of patients with MCD

Study name	Steroid tapering protocol in adult nephrotic syndrome due to MCD‐ a randomised control trial of 2 regimens
Methods	Parallel, active control RCT
Participants	Age:18 to 70 years Nephrotic syndrome and biopsy‐proven MCD Estimated number of participants: 188 patients
Interventions	Treatment group Achievement of remission with 1 mg/kg of oral prednisolone; then prednisolone tapered to stop over a period of 2 months Control group Not reported
Outcomes	Primary Time to first relapse Secondary Number of relapses Total prednisolone dose Adverse events: episodes of upper/lower respiratory tract infection, DM
Starting date	Planned 01/01/2016. Study had not commenced by January 2020
Contact information	Prof Vivekanand Jha: vjha60@gmail.com Dr Raja Ramachandran: drraja_1980@yahoo.co.in
Notes	Estimated duration of study: 3 years Information from Dr Ramachandran via email on January 18, 2020 that study was never started but may be in future

Study name	Efficacy of rituximab in comparison to continued corticosteroid treatment in idiopathic nephrotic syndrome unresponsive to 8 weeks of high dose prednisolone
Methods	Parallel, open‐label RCT
Participants	Aged ≥ 18 years with idiopathic nephrotic syndrome caused by biopsy‐proven MCD or FSGS and persistent proteinuria ≥ 2 g/24 hours or a UPCR ≥ 2 g/10 mmol (2 g/g) after 8 weeks of treatment with high dose prednisolone 1 mg/kg/day (max 80 mg/day)
Interventions	Treatment group: Rituximab (IV): 375 mg/m² on day 0 and day 14. B‐cells will be monitored weekly, and if no complete depletion is achieved additional dose(s) of rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses) Control group Prednisolone: 1 mg/kg/day (max 80 mg/day) for 8 weeks
Outcomes	Primary outcome Complete remission (time frame: 8 weeks) Secondary outcomes Partial remission, late complete or partial remission Time to remission Time to relapse Proportion of patients with relapse Proportion of patients treated with additional immunosuppressive drugs General health assessment (RAND‐36) QoL Proportion of patients with adverse events Cost‐effectiveness analysis Cost‐utility analysis Difference in kidney function Proportion of patients with increased baseline SCr ≥ 50% Benefit‐risk ratios
Starting date	January 2, 2018
Contact information	Jeroen K Deegens, MD, PhD: Jeroen.Deegens@radboudumc.nl Jack F Wetzels, MD, PhD: Jack.Wetzels@radboudumc.nl
Notes	Estimated primary completion date: January 2, 2021

Study name	A phase II randomized, placebo‐controlled, double‐blind, parallel arms with switchover, pilot study to evaluate the efficacy and safety of intravenous abatacept in treatment resistant nephrotic syndrome (focal segmental glomerulosclerosis/minimal change disease)
Methods	Placebo controlled RCT (quadruple blind)
Participants	90 patients aged ≥ 6 years with treatment‐resistant nephrotic syndrome due to MCD or FSGS (collapsing FSGS excluded); GFR ≥ 45 mL/min/1.73 m² Exclusions: Patients with recurrence of disease post‐transplant, secondary treatment‐resistant nephrotic syndrome, DM, CHF, BMI > 40, recent or chronic infections Patients stratified for age (< 18 and ≥ 18), apolipoprotein L1 risk status
Interventions	16‐week parallel arms comparing IV abatacept and placebo (normal saline) on days 1,14, 28 and then every 28 days 16‐week cross‐over with placebo group receiving abatacept and abatacept group receiving placebo 169‐day abatacept extension with all receiving abatacept Weight‐tiered dose of abatacept from 500 to 1000 mg. Children < 18 years weighing < 75 kg: 10 mg/kg/dose Standard immunosuppression (CNI, MMF, prednisolone) unchanged in 1 month, ACEi, ARB
Outcomes	Difference in % of participants who achieve a renal response by 113 days (end of first 16‐week parallel‐group study). Renal response defined as ≥ 50% reduction in UPCR from baseline to day 113 with UPCR < 3g/g and eGFR > 90 mL/min/1.73 m² (if below normal at baseline, remaining ≥ 75% of baseline) Change in proteinuria, GFR, remission, QoL(PROMIS), adverse events
Starting date	March 1, 2016. Estimated completion date June 2020
Contact information	Anna Greka: agreka@bwh.harvard.edu
Notes	27 study sites. NCT02592798. Sponsor: Bristol‐Myers Squibb

Study name	The use of rituximab in the treatment of nephrotic glomerulonephritis (TURING)
Methods	A randomised, two‐arm (1:1 ratio), double blind, placebo controlled phase III trial
Participants	112 participants aged 16 years or over with de novo or relapsing nephrotic syndrome with MCD or FSGS
Interventions	Treatment group Rituximab for 3 doses (1 g/dose) and prednisolone Control group Placebo and prednisolone
Outcomes	The primary endpoint will be time from partial remission to relapse Follow‐up will continue until all patients have completed at least 24 months of follow‐up or have relapsed
Starting date	Recruitment start date 01/07/2019
Contact information	Cambridge Clinical Trials Unit based at Cambridge University Hospitals NHS Foundation Trust. Ms Sonakshi Kadyan (scientific): sonakshi.kadyan@addenbrookes.nhs.uk
Notes	Recruitment end date 30/12/2024. End date of study 30/12/2025

PERMALINK

Interventions for minimal change disease in adults with nephrotic syndrome

Karolis Azukaitis

Suetonia C Palmer

Giovanni FM Strippoli

Elisabeth M Hodson

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

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

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

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Ongoing studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Steroids versus no specific treatment for minimal change disease in adults with nephrotic syndrome.

Summary of findings 2. Intravenous ± oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome.

Summary of findings 3. Calcineurin inhibitors ± oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome.

Summary of findings 4. Mycophenolate sodium + oral steroids versus oral steroids alone for minimal change disease in adults with nephrotic syndrome.

Steroids versus no treatment

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

Intravenous steroids ± oral steroids versus oral steroids

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.