IgA nephropathy and glucocorticoids—a limbo dance?

In this issue of Kidney International, arguments are presented for and against the use of systemic glucocorticoids (GCs) in the treatment of IgA nephropathy (IgAN) that is likely to progress. The use of immunomodulation in IgAN makes sense. The immune system, especially the mucosal immune system, appears to be involved in disease pathogenesis. Immune deposits accumulate in the glomerular mesangium and almost certainly activate inflammatory pathways, including complement, resulting in acute kidney damage that heals with scar and often progresses to chronic damage. Within this mechanistic framework, although IgAN is certainly an immune disease, in most instances, it is not a highly inflammatory disease. Zhang et al.1Zhang Y.-M. Lv J.-C. Wong M.G. et al.Glucocorticoids for IgA nephropathy—pro.Kidney Int. 2023; 103: 666-669Abstract Full Text Full Text PDF Scopus (1) Google Scholar present a compelling argument that GCs are effective in IgAN. GCs are immunomodulatory, and high doses are anti-inflammatory, but in a disease with mild-to-moderate inflammation, high GC dosing may not be needed. Indeed, Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) showed that lower-dose prednisolone was as effective as high-dose prednisolone. But as Cheung and Barratt2Cheung C.K. Barratt J. First do no harm: systemic glucocorticoids should not be used for the treatment of progressive IgA nephropathy.Kidney Int. 2023; 103: 669-673Abstract Full Text Full Text PDF Scopus (1) Google Scholar counter, even modest-dose systemic GC administration is fraught with side effects, albeit fewer than high-dose. Moreover, Cheung and Barratt correctly point out that IgAN is a chronic disease, likely to become “active” again after systemic GCs are stopped. Repeated courses or long-term use of even moderate-dose systemic GCs is not desirable. Enter Nefecon, a specially packaged formulation of enteric budesonide shown to be effective in IgAN. Nefecon administration results in very low systemic GC exposure and is postulated to mainly work locally on the gut immune system at an early step in the pathogenesis of IgAN. With minimal systemic GC side effects, it is conceivable that if repeated treatments for IgAN are necessary to control disease activity, Nefecon may be tolerated. All controversies aside, the authors on both sides of this debate agree that a holistic way to manage IgAN, targeting pathogenesis, inflammation, and fibrosis, is needed, that several ongoing trials are addressing these issues without systemic GCs, and that going as low as we can with the GC dosing bar is a critical goal. First do no harm: systemic glucocorticoids should not be used for the treatment of progressive IgA nephropathyKidney InternationalVol. 103Issue 4PreviewOver recent years, significant progress has been made in the understanding of the pathogenesis of IgA nephropathy (IgAN). A multihit model is widely accepted; in patients with IgAN, there is an increase in circulating poorly galactosylated IgA1, likely to be of mucosal origin, that drives autoantibody production, immune complex formation, and deposition of these poorly galactosylated IgA1-containing immune complexes within the glomerular mesangium, resulting in inflammation and progressive kidney damage. Full-Text PDF Glucocorticoids for IgA nephropathy—proKidney InternationalVol. 103Issue 4PreviewSince IgA nephropathy (IgAN) was first described in 1968 by Jean Berger, supportive lifestyle measures and blood pressure lowering agents, especially renin-angiotensin system inhibitors (RASi), have become first-line treatment. Despite this, a substantial risk of progression remains even when these therapies are optimally employed.1 This is important as these supportive therapies, and more recently sodium-glucose cotransporter-2 inhibitors,2 do not address the underlying cause of IgAN. Full-Text PDF