Top

BMC Nephrology

Published in:

Open Access 01-12-2019 | Research article

Efficacy and safety of immunosuppressive treatment in IgA nephropathy: a meta-analysis of randomized controlled trials

Authors: Zheng Zhang, Yue Yang, Shi-min Jiang, Wen-ge Li

Published in: BMC Nephrology | Issue 1/2019

Abstract

Background

Immunosuppressive agents have been widely used in the treatment of IgA nephropathy (IgAN), but the efficacy and safety remain controversial. The recent STOP-IgAN and TESTING studies have again focused attention on the application of immunosuppressive agents in IgAN. This study investigated the benefits and risks of immunosuppressive agents in IgAN.

Methods

MEDLINE, EMBASE, the Cochrane Library, and article reference lists were searched for randomized controlled trials (RCTs) comparing immunosuppressive agents with any other non-immunosuppressive agents for treating IgAN. A meta-analysis was performed on the outcomes of proteinuria, creatinine (Cr), estimated glomerular filtration rate (eGFR), and adverse events in patients with IgAN, and trial sequential analyses were also performed for outcomes.

Results

Twenty-nine RCTs (1957 patients) that met our inclusion criteria were identified. Steroids (weighted mean difference [WMD] –0.70, 95% confidence interval [CI] –1.2 to − 0.20), non-steroidal immunosuppressive agents (NSI) (WMD –0. 43, 95% CI − 0.55 to − 0.31), and combined steroidal and non-steroidal immunosuppressive agents (S&NSI) (WMD –1.46, 95% CI − 2.13 to − 0.79) therapy significantly reduced proteinuria levels compared with the the control group. Steroid treatment significantly reduced the risk of end-stage renal disease (ESRD) (relative risk [RR] 0.39, CI 0.19 to 0.79) compared with the control group. The immunosuppressive therapy group showed significant increases in gastrointestinal, hematological, dermatological, and genitourinary side effects, as well as impaired glucose tolerance or diabetes. Hyperkalemia was more common in the control group.

Conclusion

Immunosuppressive therapy can significantly reduce proteinuria and ESRD risk in patients with IgAN, but with a concomitant increase in adverse reactions. Therefore, care is required in the application of immunosuppressive agents in IgAN.

Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402–14.PubMedCrossRef

McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414–30.PubMedCrossRef

Cattran DC, Feehally J, Cook HT, Liu ZH, Fervenza FC, Mezzano SA, et al. Kidney disease : improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2012;2(2):139–274.

J.P.T. Higgins G. Cochrane Handbook for systematic reviews of interventions, version 5.1.0. 2011. Available from: http://www.cochrane.org/handbook.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339.PubMedPubMedCentralCrossRef

Higgins J GS. Cochrane handbook for systematic reviews of interventions version 5.0. 2 [updated September 2009]. The Cochrane Collaboration, 2009. 2010; Available from www.cochrane-handbook.org.

Wong SS, Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc. 2006;94(1):41–7.PubMedPubMedCentral

Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.PubMedPubMedCentralCrossRef

Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61(1):64–75.PubMedCrossRef

10.

Ballardie FW, Roberts ISD. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol. 2002;13(1):142–8.PubMed

11.

Cheng G, Liu D, Margetts P, Liu L, Zhao Z, Liu Z, et al. Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin a nephropathy. Nephrology (Carlton). 2015;20(2):77–84.CrossRef

12.

Cruzado JM, Poveda R, Ibernón M, Díaz M, Fulladosa X, Carrera M, et al. Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy. Nephrol Dial Transplant. 2011;26(11):3596–602.PubMedCrossRef

13.

Frisch G, Lin J, Rosenstock J, Markowitz G, D’Agati V, Radhakrishnan J, et al. Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant. 2005; 20(10):[2139–2145]. Available from: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/999/CN-00528999/frame.html.CrossRef

14.

Harmankaya O, Ozturk Y, Basturk T, Obek A, Kilicarslan I. Efficacy of immunosuppressive therapy in IgA nephropathy presenting with isolated hematuria. Int Urol Nephrol. 2002;33(1):167–71.PubMedCrossRef

15.

Hirai K, Ookawara S, Kitano T, Miyazawa H, Ito K, Ueda Y, et al. Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin a nephropathy: a randomized controlled trial. Kidney Res Clin Pract. 2017;36(2):159–66.PubMedPubMedCentralCrossRef

16.

Hogg RJ, Bay RC, Jennette JC, Sibley R, Kumar S, Fervenza FC, et al. Randomized controlled trial of mycophenolate Mofetil in children, adolescents, and adults with IgA nephropathy. Am J Kidney Dis. 2015;66(5):783–91.PubMedCrossRef

17.

Julian BA, Barker C. Alternate-day prednisone therapy in IgA nephropathy. Preliminary analysis of a prospective, randomized, controlled trial. Contrib Nephrol. 1993;104:198–206.PubMedCrossRef

18.

Yoshikawa N, Ito H, Sakai T, Takekoshi Y, Honda M, Awazu M, et al. A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. J Am Soc Nephrol. 1999;10(1):101–9.PubMed

19.

Katafuchi R, Ikeda K, Mizumasa T, Tanaka H, Ando T, Yanase T, et al. Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy. Am J Kidney Dis. 2003;41(5):972–83.PubMedCrossRef

20.

Kim YC, Chin HJ, Koo HS, Kim S. Tacrolimus decreases albuminuria in patients with IgA nephropathy and normal blood pressure: a double-blind randomized controlled trial of efficacy of tacrolimus on IgA nephropathy. PLoS One. 2013;8(8):e71545.PubMedPubMedCentralCrossRef

21.

Koike M, Takei T, Uchida K, Honda K, Moriyama T, Horita S, et al. Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center. Clin Exp Nephrol. 2008;12(4):250–5.PubMedCrossRef

22.

Pozzi C, Bolasco P, Fogazzi G, Andrulli S, Altieri P, Ponticelli C, et al. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet. 1999;353(9156):883–7.PubMedCrossRef

23.

Lai KN, Lai FM, Ho CP, Chan KW. Corticosteroid therapy in IgA nephropathy with nephrotic sydrome: a long-term controlled trial. Clin Nephrol. 1986;26(4):174–80.PubMed

24.

Lv J, Zhang H, Chen Y, Li G, Jiang L, Singh AK, et al. Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2009;53(1):26–32.PubMedCrossRef

25.

Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, et al. Effect of Oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA. 2017;318(5):432–42.PubMedPubMedCentralCrossRef

26.

Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, et al. Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study. Kidney Int. 2004;65(5):1842–9.PubMedCrossRef

27.

Manno C, Torres DD, Rossini M, Pesce F, Schena FP. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant. 2009;24(12):3694–701.PubMedCrossRef

28.

Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med. 2015;373(23):2225–36.PubMedCrossRef

29.

Shoji T, Nakanishi I, Suzuki A, Hayashi T, Togawa M, Okada N, et al. Early treatment with corticosteroids ameliorates proteinuria, proliferative lesions, and mesangial phenotypic modulation in adult diffuse proliferative IgA nephropathy. Am J Kidney Dis. 2000;35(2):194–201.PubMedCrossRef

30.

Tang S, Leung JC, Chan LY, Lui YH, Tang CS, Kan CH, et al. Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney Int. 2005;68(2):802–12 Available from: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/164/CN-00523164/frame.html.PubMedCrossRef

31.

Walker RG, Yu SH, Owen JE, Kincaid-Smith P. The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial. Clin Nephrol. 1990;34(3):103–7.PubMed

32.

Wu J, Duan SW, Sun XF, Li WG, Wang YP, Liu WH, et al. Efficacy of Leflunomide, Telmisartan, and Clopidogrel for immunoglobulin a nephropathy: a randomized controlled trial. Chin Med J. 2016;129(16):1894–903.PubMedPubMedCentralCrossRef

33.

Xie Y, Huang S, Wang L, Miao L, Zhang A, Li Y, et al. Efficacy and safety of mizoribine combined with losartan in the treatment of IgA nephropathy: a multicenter, randomized, controlled study. Am J Med Sci. 2011;341(5):367–72 Available from: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/297/CN-00787297/frame.html.PubMedCrossRef

34.

Woo KT, Edmondson RP, Yap HK, Wu AY, Chiang GS, Lee EJ, et al. Effects of triple therapy on the progression of mesangial proliferative glomerulonephritis. Clin Nephrol. 1987;27(2):56–64.PubMed

35.

Kamei K, Nakanishi K, Ito S, Saito M, Sako M, Ishikura K, et al. Long-term results of a randomized controlled trial in childhood IgA nephropathy. Clin J Am Soc Nephrol. 2011;6(6):1301–7.PubMedPubMedCentralCrossRef

36.

Locatelli F, Pozzi C, Del Vecchio L, Bolasco PG, Fogazzi GB, Andrulli S, et al. Role of proteinuria reduction in the progression of IgA nephropathy. Ren Fail. 2001;23(3–4):495–505.PubMedCrossRef

37.

Pozzi C, Andrulli S, Del Vecchio L, Melis P, Fogazzi GB, Altieri P, et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol. 2004;15(1):157–63.PubMedCrossRef

38.

Tang SCW, Tang AWC, Wong SSH, Leung JCK, Ho YW, Lai KN. Long-term study of mycophenolate mofetil treatment in IgA nephropathy. Kidney Int. 2010;77(6):543–9.PubMedCrossRef

39.

Farnsworth EB. Metabolic changes associated with administration of adrenocorticotropin in the nephrotic syndrome. Proc Soc Exp Biol Med. 1950;74(1):60–2.PubMedCrossRef

40.

Barnett HL, Mc NH, Mc CW, Forman C, Rapoport M, Michie A, et al. The effects of ACTH and cortisone on the nephrotic syndrome. AMA Am J Dis Child. 1950;80(3):519–20.PubMed

41.

Chasis H, Goldring W, Baldwin DS. Effect of febrile plasma, typhoid vaccine and nitrogen mustard on renal manifestations of human glomerulonephritis. Proc Soc Exp Biol Med. 1949;71(4):565–7.PubMedCrossRef

42.

Zhou YH, Tang LG, Guo SL, Jin ZC, Wu MJ, Zang JJ, et al. Steroids in the treatment of IgA nephropathy to the improvement of renal survival: a systematic review and meta-analysis. PLoS One. 2011;6(4):e18788.PubMedPubMedCentralCrossRef

43.

Lv J, Xu D, Perkovic V, Ma X, Johnson DW, Woodward M, et al. Corticosteroid therapy in IgA nephropathy. J Am Soc Nephrol. 2012;23(6):1108–16.PubMedPubMedCentralCrossRef

44.

Cheng J, Zhang X, Zhang W, He Q, Tao X, Chen J. Efficacy and safety of glucocorticoids therapy for IgA nephropathy: a meta-analysis of randomized controlled trials. Am J Nephrol. 2009;30(4):315–22.PubMedCrossRef

45.

Ponticelli C, Glassock RJ. Prevention of complications from use of conventional immunosuppressants: a critical review. J Nephrol. 2019.

Title: Efficacy and safety of immunosuppressive treatment in IgA nephropathy: a meta-analysis of randomized controlled trials
Authors: Zheng Zhang
Yue Yang
Shi-min Jiang
Wen-ge Li
Publication date: 01-12-2019
Publisher: BioMed Central
Published in: BMC Nephrology / Issue 1/2019
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-019-1519-3

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Efficacy and safety of immunosuppressive treatment in IgA nephropathy: a meta-analysis of randomized controlled trials

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2019

Typing of hereditary renal amyloidosis presenting with isolated glomerular amyloid deposition

Improved long-term survival with home hemodialysis compared with institutional hemodialysis and peritoneal dialysis: a matched cohort study

Efficacy and safety of cyclosporine a for patients with steroid-resistant nephrotic syndrome: a meta-analysis

Rapid decline of renal function in patients with type 2 diabetes with heavy proteinuria: a report of three cases

Joint associations of obesity and estimated GFR with clinical outcomes: a population-based cohort study

Association of estimated dietary acid load with albuminuria in Japanese adults: a cross-sectional study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page