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REVIEW article

Front. Nephrol.
Sec. Glomerular disease
Volume 3 - 2023 | doi: 10.3389/fneph.2023.1346769
This article is part of the Research Topic

IgA Nephropathy: a Nephrologist’s Challenge in 2023

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The Role of BAFF and APRIL in IgA Nephropathy: Pathogenic Mechanisms and Targeted Therapies

Chee Kay Cheung1, 2* Jonathan Barratt1, 2 Adrian Liew3 Hong Zhang4 Vladimir Tesar5 Richard Lafayette6
  • 1Department of Cardiovascular Sciences, School of Medicine, College of Life Sciences, University of Leicester, United Kingdom
  • 2John Walls Renal Unit, Leicester General Hospital, United Kingdom
  • 3Mount Elizabeth Novena Hospital, Singapore
  • 4Department of Nephrology, First Hospital, Peking University, China
  • 5Department of Nephrology, First Faculty of Medicine, Charles University, Czechia
  • 6Department of Medicine, School of Medicine, Stanford University, United States

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Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The "four-hit hypothesis" of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.

Keywords: B-cell activating factor BAFF, a proliferation-inducing ligand APRIL, IgA nephropathy, Dual inhibition, Atacicept

Received: 29 Nov 2023; Accepted: 31 Dec 2023.

Copyright: © 2023 Cheung, Barratt, Liew, Zhang, Tesar and Lafayette. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Chee Kay Cheung, Department of Cardiovascular Sciences, School of Medicine, College of Life Sciences, University of Leicester, Leicester, LE1 7RH, East Midlands, United Kingdom