Novel Treatment Paradigms: Primary IgA Nephropathy

Overview

Journal Kidney Int Rep

Publisher Elsevier

Specialty Nephrology

Date 2024 Feb 12

PMID 38344739

Authors

Haresh Selvaskandan

Jonathan Barratt

Chee Kay Cheung

Affiliations

Soon will be listed here.

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this scheme. Advancing insights into the pathophysiology of IgAN, including the roles of the mucosal immune system, B-cells, the complement system, and the endothelin system have driven development of therapies that target these factors. This review outlines current, recently approved, and emerging therapies for IgAN.

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References

Fellstrom B, Barratt J, Cook H, Coppo R, Feehally J, De Fijter J . Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017; 389(10084):2117-2127. DOI: 10.1016/S0140-6736(17)30550-0. View

Herrington W, Staplin N, Wanner C, Green J, Hauske S, Emberson J . Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2022; 388(2):117-127. PMC: 7614055. DOI: 10.1056/NEJMoa2204233. View

Gale D, Molyneux K, Wimbury D, Higgins P, Levine A, Caplin B . Galactosylation of IgA1 Is Associated with Common Variation in . J Am Soc Nephrol. 2017; 28(7):2158-2166. PMC: 5491291. DOI: 10.1681/ASN.2016091043. View

Selvaskandan H, Cheung C, Muto M, Barratt J . New strategies and perspectives on managing IgA nephropathy. Clin Exp Nephrol. 2019; 23(5):577-588. PMC: 6469670. DOI: 10.1007/s10157-019-01700-1. View

Sallustio F, Curci C, Chaoul N, Fonto G, Lauriero G, Picerno A . High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients. Nephrol Dial Transplant. 2020; 36(3):452-464. PMC: 7898021. DOI: 10.1093/ndt/gfaa264. View

Kloster Smerud H, Barany P, Lindstrom K, Fernstrom A, Sandell A, Pahlsson P . New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria. Nephrol Dial Transplant. 2011; 26(10):3237-42. DOI: 10.1093/ndt/gfr052. View

Hou F, Xie D, Wang J, Xu X, Yang X, Ai J . Effectiveness of Mycophenolate Mofetil Among Patients With Progressive IgA Nephropathy: A Randomized Clinical Trial. JAMA Netw Open. 2023; 6(2):e2254054. DOI: 10.1001/jamanetworkopen.2022.54054. View

Lv J, Zhang H, Wong M, Jardine M, Hladunewich M, Jha V . Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017; 318(5):432-442. PMC: 5817603. DOI: 10.1001/jama.2017.9362. View

Lv J, Wong M, Hladunewich M, Jha V, Hooi L, Monaghan H . Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022; 327(19):1888-1898. PMC: 9115617. DOI: 10.1001/jama.2022.5368. View

10.

MacLennan I, Vinuesa C . Dendritic cells, BAFF, and APRIL: innate players in adaptive antibody responses. Immunity. 2002; 17(3):235-8. DOI: 10.1016/s1074-7613(02)00398-9. View

11.

Nakamura T, Ebihara I, Fukui M, Tomino Y, Koide H . Effect of a specific endothelin receptor A antagonist on glomerulonephritis of ddY mice with IgA nephropathy. Nephron. 1996; 72(3):454-60. DOI: 10.1159/000188912. View

12.

Lafayette R, Kristensen J, Stone A, Floege J, Tesar V, Trimarchi H . Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet. 2023; 402(10405):859-870. DOI: 10.1016/S0140-6736(23)01554-4. View

13.

Uffing A, Perez-Saez M, Jouve T, Bugnazet M, Malvezzi P, Muhsin S . Recurrence of IgA Nephropathy after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2021; 16(8):1247-1255. PMC: 8455056. DOI: 10.2215/CJN.00910121. View

14.

Zhang H, Rizk D, Perkovic V, Maes B, Kashihara N, Rovin B . Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int. 2023; 105(1):189-199. DOI: 10.1016/j.kint.2023.09.027. View

15.

Litinskiy M, Nardelli B, Hilbert D, He B, Schaffer A, Casali P . DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol. 2002; 3(9):822-9. PMC: 4621779. DOI: 10.1038/ni829. View

16.

Kedzierski R, Yanagisawa M . Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001; 41:851-76. DOI: 10.1146/annurev.pharmtox.41.1.851. View

17.

Cheung C, Dormer J, Barratt J . The role of complement in glomerulonephritis-are novel therapies ready for prime time?. Nephrol Dial Transplant. 2022; 38(8):1789-1797. DOI: 10.1093/ndt/gfac296. View

18.

Zhai Y, Zhu L, Shi S, Liu L, Lv J, Zhang H . Increased APRIL Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy. Medicine (Baltimore). 2016; 95(11):e3099. PMC: 4839931. DOI: 10.1097/MD.0000000000003099. View

19.

Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M . Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014; 46(11):1187-96. PMC: 4213311. DOI: 10.1038/ng.3118. View

20.

Heerspink H, Stefansson B, Correa-Rotter R, Chertow G, Greene T, Hou F . Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020; 383(15):1436-1446. DOI: 10.1056/NEJMoa2024816. View