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Immunosuppressive agents for treating IgA nephropathy.
Cochrane Database Syst Rev. 2020 03 12; 3:CD003965.CD

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.

Authors+Show Affiliations

University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy. The University of Sydney, Sydney School of Public Health, Sydney, Australia.University of Otago Christchurch, Department of Medicine, 2 Riccarton Ave, PO Box 4345, Christchurch, New Zealand, 8140.University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy. The University of Sydney, Sydney School of Public Health, Sydney, Australia.University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy. The University of Sydney, Sydney School of Public Health, Sydney, Australia.The Children's Hospital at Westmead, Cochrane Kidney and Transplant, Centre for Kidney Research, Westmead, NSW, Australia, 2145. Flinders University, College of Medicine and Public Health, Adelaide, SA, Australia, 5001.Danone Research, RD 128, Palaiseau Cedex, France, 91767.UT-Houston Health Science Center, Division of Pediatric Nephrology and Hypertension, 6431 Fannin Street, MSB 3-121, Houston, TX, USA, 77030.UT-Houston Health Science Center, Internal Medicine, Division of Renal Diseases and Hypertension, 64312 Fannin St, Houston, TX, USA, 77030.University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy.University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy. The University of Sydney, Sydney School of Public Health, Sydney, Australia. The Children's Hospital at Westmead, Cochrane Kidney and Transplant, Centre for Kidney Research, Westmead, NSW, Australia, 2145.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

Language

eng

PubMed ID

32162319

Citation

Natale, Patrizia, et al. "Immunosuppressive Agents for Treating IgA Nephropathy." The Cochrane Database of Systematic Reviews, vol. 3, 2020, p. CD003965.
Natale P, Palmer SC, Ruospo M, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev. 2020;3:CD003965.
Natale, P., Palmer, S. C., Ruospo, M., Saglimbene, V. M., Craig, J. C., Vecchio, M., Samuels, J. A., Molony, D. A., Schena, F. P., & Strippoli, G. F. (2020). Immunosuppressive agents for treating IgA nephropathy. The Cochrane Database of Systematic Reviews, 3, CD003965. https://doi.org/10.1002/14651858.CD003965.pub3
Natale P, et al. Immunosuppressive Agents for Treating IgA Nephropathy. Cochrane Database Syst Rev. 2020 03 12;3:CD003965. PubMed PMID: 32162319.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunosuppressive agents for treating IgA nephropathy. AU - Natale,Patrizia, AU - Palmer,Suetonia C, AU - Ruospo,Marinella, AU - Saglimbene,Valeria M, AU - Craig,Jonathan C, AU - Vecchio,Mariacristina, AU - Samuels,Joshua A, AU - Molony,Donald A, AU - Schena,Francesco Paolo, AU - Strippoli,Giovanni Fm, Y1 - 2020/03/12/ PY - 2021/03/12/pmc-release PY - 2020/3/13/entrez PY - 2020/3/13/pubmed PY - 2020/8/1/medline SP - CD003965 EP - CD003965 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev VL - 3 N2 - 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. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/32162319/Immunosuppressive_agents_for_treating_IgA_nephropathy_ L2 - https://doi.org/10.1002/14651858.CD003965.pub3 DB - PRIME DP - Unbound Medicine ER -