Multicentre Clinical Study to Evaluate the Effect of Personalized Therapy on Patients With Immunoglobulin A Nephropathy.

Summary

Idiopathic immunoglobulin A nephropathy (IgAN) is the most common biopsy-proven glomerulonephritis in the world. Approximately 40% of IgAN patients reach end-stage kidney disease (ESKD) 20 years after their kidney biopsy. The high prevalence of ESKD suggests the need to move from a generalized therapy for all patients to personalized therapy. Many RCTs have been conducted stratifying patients based on the laboratory findings (serum creatinine, eGFR and daily proteinuria). In contrast, data from the kidney biopsy has been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have not been equally distributed in experimental and control arms of the randomized clinical trials (RCTs) Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label randomized clinical trial based on patients' stratification at the time of their kidney biopsy. The investigators will consider, first, the type of renal lesions followed by the serum creatinine values, eGFR and proteinuria. IgAN patients with active renal lesions (n=132) will be enrolled in the first RCT (ACIgAN) in which they will receive corticosteroids (pulse therapy) plus oral corticosteroids combined with RASB or RASB followed by oral corticosteroids. IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic renal disease (n=294) will be enrolled in the second RCT (CHRONIgAN) in which they will receive the SGLT2 inhibitor combined with RASB compared with RASB combined with oral corticosteroids. Using this approach, the investigators hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time. Recently, we developed a Clinical Decision Support System (CDSS) tool using artificial intelligence (artificial neural networks) to identify IgAN patients at high risk of developing ESKD. The IgAN tool (DialCheck) was validated in a retrospective cohort of IgAN patients but not in a prospective clinical study. The investigators propose to measure the power of the DiaCheck tool in patients enrolled in both RCTs to determine whether personalized therapy can slow the decline of the renal function to delay the ESKD. The CLIgAN study also includes a cutting-edge molecular study for precision therapy (PRECIgAN).

Timeline

Start

2023-05-01

Primary completion

2026-06-01

Completion

2028-12-31

Publications

• Results Schena FP, Nistor I. Epidemiology of IgA Nephropathy: A Global Perspective. Semin Nephrol. 2018 Sep;38(5):435-442. doi: 10.1016/j.semnephrol.2018.05.013.
• Results Koyama A, Igarashi M, Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases. Am J Kidney Dis. 1997 Apr;29(4):526-32. doi: 10.1016/s0272-6386(97)90333-4.
• Results Manno C, Strippoli GF, D'Altri C, Torres D, Rossini M, Schena FP. A novel simpler histological classification for renal survival in IgA nephropathy: a retrospective study. Am J Kidney Dis. 2007 Jun;49(6):763-75. doi: 10.1053/j.ajkd.2007.03.013.
• Results Chapter 10: Immunoglobulin A nephropathy. Kidney Int Suppl (2011). 2012 Jun;2(2):209-217. doi: 10.1038/kisup.2012.23. No abstract available.
• Results Schena FP, Anelli VW, Trotta J, Di Noia T, Manno C, Tripepi G, D'Arrigo G, Chesnaye NC, Russo ML, Stangou M, Papagianni A, Zoccali C, Tesar V, Coppo R; members of the VALIGA study. Development and testing of an artificial intelligence tool for predicting end-stage kidney disease in patients with immunoglobulin A nephropathy. Kidney Int. 2021 May;99(5):1179-1188. doi: 10.1016/j.kint.2020.07.046. Epub 2020 Sep 2.
• Results Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D'Agati V, D'Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009 Sep;76(5):546-56. doi: 10.1038/ki.2009.168. Epub 2009 Jul 1.
• Results Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009 Sep;76(5):534-45. doi: 10.1038/ki.2009.243. Epub 2009 Jul 1.
• Results Kang SH, Choi SR, Park HS, Lee JY, Sun IO, Hwang HS, Chung BH, Park CW, Yang CW, Kim YS, Choi YJ, Choi BS. The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. Nephrol Dial Transplant. 2012 Jan;27(1):252-8. doi: 10.1093/ndt/gfr295. Epub 2011 May 23.
• Results Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, Panzer U, Peters H, Benck U, Mertens PR, Kuhlmann U, Witzke O, Gross O, Vielhauer V, Mann JF, Hilgers RD, Floege J; STOP-IgAN Investigators. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015 Dec 3;373(23):2225-36. doi: 10.1056/NEJMoa1415463.
• Results Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, Monaghan H, Zhao M, Barbour S, Reich H, Cattran D, Glassock R, Levin A, Wheeler D, Woodward M, Billot L, Chan TM, Liu ZH, Johnson DW, Cass A, Feehally J, Floege J, Remuzzi G, Wu Y, Agarwal R, Wang HY, Perkovic V; TESTING Study Group. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017 Aug 1;318(5):432-442. doi: 10.1001/jama.2017.9362.
• Results Shen XH, Liang SS, Chen HM, Le WB, Jiang S, Zeng CH, Zhou ML, Zhang HT, Liu ZH. Reversal of active glomerular lesions after immunosuppressive therapy in patients with IgA nephropathy: a repeat-biopsy based observation. J Nephrol. 2015 Aug;28(4):441-9. doi: 10.1007/s40620-014-0165-x. Epub 2015 Jan 14.
• Results Shi SF, Wang SX, Jiang L, Lv JC, Liu LJ, Chen YQ, Zhu SN, Liu G, Zou WZ, Zhang H, Wang HY. Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification. Clin J Am Soc Nephrol. 2011 Sep;6(9):2175-84. doi: 10.2215/CJN.11521210. Epub 2011 Aug 18.
• Results Lv J, Yang Y, Zhang H, Chen W, Pan X, Guo Z, Wang C, Li S, Zhang J, Zhang J, Liu L, Shi S, Wang S, Chen M, Cui Z, Chen N, Yu X, Zhao M, Wang H. Prediction of outcomes in crescentic IgA nephropathy in a multicenter cohort study. J Am Soc Nephrol. 2013 Dec;24(12):2118-25. doi: 10.1681/ASN.2012101017. Epub 2013 Sep 12.
• Results Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang H, Feehally J; IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017 May;91(5):1014-1021. doi: 10.1016/j.kint.2017.02.003. Epub 2017 Mar 22.
• Results Levey AS, Eckardt KU, Dorman NM, Christiansen SL, Hoorn EJ, Ingelfinger JR, Inker LA, Levin A, Mehrotra R, Palevsky PM, Perazella MA, Tong A, Allison SJ, Bockenhauer D, Briggs JP, Bromberg JS, Davenport A, Feldman HI, Fouque D, Gansevoort RT, Gill JS, Greene EL, Hemmelgarn BR, Kretzler M, Lambie M, Lane PH, Laycock J, Leventhal SE, Mittelman M, Morrissey P, Ostermann M, Rees L, Ronco P, Schaefer F, St Clair Russell J, Vinck C, Walsh SB, Weiner DE, Cheung M, Jadoul M, Winkelmayer WC. Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference. Kidney Int. 2020 Jun;97(6):1117-1129. doi: 10.1016/j.kint.2020.02.010. Epub 2020 Mar 9.
• Results Orlandi PF, Xie D, Yang W, Cohen JB, Deo R, Ricardo AC, Schrauben S, Wang X, Hamm LL, He J, Sondheimer JH, Kallem K, Townsend R, Raj D, Parsa A, Anderson AH, Feldman HI; CRIC Study Investigators; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Slope of Kidney Function and Its Association with Longitudinal Mortality and Cardiovascular Disease among Individuals with CKD. J Am Soc Nephrol. 2020 Dec;31(12):2912-2923. doi: 10.1681/ASN.2020040476. Epub 2020 Oct 6.
• Results Reich HN, Troyanov S, Scholey JW, Cattran DC; Toronto Glomerulonephritis Registry. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007 Dec;18(12):3177-83. doi: 10.1681/ASN.2007050526. Epub 2007 Oct 31.
• Results Lea J, Greene T, Hebert L, Lipkowitz M, Massry S, Middleton J, Rostand SG, Miller E, Smith W, Bakris GL. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern Med. 2005 Apr 25;165(8):947-53. doi: 10.1001/archinte.165.8.947.
• Results Levin A, Agarwal R, Herrington WG, Heerspink HL, Mann JFE, Shahinfar S, Tuttle KR, Donner JA, Jha V, Nangaku M, de Zeeuw D, Jardine MJ, Mahaffey KW, Thompson AM, Beaucage M, Chong K, Roberts GV, Sunwold D, Vorster H, Warren M, Damster S, Malik C, Perkovic V; participant authors of the International Society of Nephrology's 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020 Oct;98(4):849-859. doi: 10.1016/j.kint.2020.07.013.
• Results Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
• Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.
• Tunnicliffe DJ, Reid S, Craig JC, Samuels JA, Molony DA, Strippoli GF. Non-immunosuppressive treatment for IgA nephropathy. Cochrane Database Syst Rev. 2024 Feb 1;2(2):CD003962. doi: 10.1002/14651858.CD003962.pub3.
• El Karoui K, Fervenza FC, De Vriese AS. Treatment of IgA Nephropathy: A Rapidly Evolving Field. J Am Soc Nephrol. 2024 Jan 1;35(1):103-116. doi: 10.1681/ASN.0000000000000242. Epub 2023 Sep 29.

Drugs

Indications