An Update on Current Therapeutic Options in IgA Nephropathy

Abstract

Immunoglobulin A nephropathy (IgAN) remains the leading cause of primary glomerular disease worldwide. Outcomes are poor with high rates of progressive chronic kidney disease and kidney failure, which contributes to global healthcare costs. Although this disease entity has been described, there were no disease-specific treatments until recently, with the current standard of care focusing on optimal supportive measures including lifestyle modifications and optimization of the renin-angiotensin-aldosterone blockade. However, with significant advances in the understanding of the pathogenesis of IgAN in the past decade, and the acceptance of surrogate outcomes for accelerated drug approval, there have been many new investigational agents tested to target this disease. As these agents become available, we envision a multi-pronged treatment strategy that simultaneously targets the consequences of ongoing nephron loss, stopping any glomerular inflammation, inhibiting pro-fibrotic signals in the glomerulus and tubulo-interstitium, and inhibiting the production of pathogenic IgA molecules. This review is an update on a previous review published in 2021, and we aim to summarize the developments and updates in therapeutic strategies in IgAN and highlight the promising discoveries that are likely to add to our armamentarium.

Keywords: IgA; IgA nephropathy; clinical trials; glomerular diseases; therapy; treatment.

Figure 1

Proposed four-hit hypothesis of IgAN pathogenesis and current therapeutic options. (1) B cell priming and activation in the mucosa-associated lymphoid tissue including Peyer’s patches concentrated in the terminal ileum, resulting in the production of Galactose-deficient IgA1 (Gd-IgA1). (2) Formation of autoantibodies against IgA1 (anti-Gd-IgA1 antibodies). (3) Formation of circulating immune complexes as IgG anti-IgA1 antibodies bind to the hinge region of Gd-IgA1. (4) Deposition of circulating immune complexes in the mesangium through mesangial trapping, which triggers downstream complement activation, tissue injury, and damage. BAFF: B Cell Activating Factor; APRIL: A Proliferation-inducing Ligand; SGLT2 inhibitors: Sodium-glucose cotransporter-2 inhibitors.

Figure 2

Pillars of IgAN Treatment. The management of patients with IgAN requires a multi-pronged approach to target the predominant pathogenic pathways specific to each patient at each disease timepoint, on top of a cornerstone of optimal supportive care. (1) Mitigation of the consequences of ongoing nephron loss through optimal RAAS blockade, SGLT2 inhibitors, endothelin receptor antagonists, and mineralocorticoid antagonists. (2) Halting glomerular inflammation through the use of systemic glucocorticoid therapy has been long studied for use in IgAN but offers short-term efficacy and comes with significant side effects. With a better understanding of IgAN being an immune mediated disease with activation of the alternative and lectin pathways mediating inflammation, complement pathway inhibitors may be an alternative to limit glomerular inflammation and injury in IgAN. (3) B cells are central to the pathogenesis of IgAN through the production of pathogenic Gd-IgA1. The use of TRF-budesonide can inhibit mucosal IgA production within Peyer’s patches with reduced systemic side effects of glucocorticoid therapy. B cell modulating therapies that inhibit BAFF and APRIL to reduce B cell proliferation and survival, as well as B cell depleting therapies such as borteozomib or felzartamab, may be useful in targeting B cell dysregulation. (4) There are no approved therapies for stopping pro-fibrotic signals in the kidney on the horizon, but we are hopeful for new therapeutic strategies to develop in the future. Gd-IgA1: Galactose-deficient IgA1; SGLT2 inhibitors: RAAS: renin-angiotensin-aldosterone system; Sodium-glucose cotransporter-2 inhibitors; TRF-budesonide: Targeted Release Formulation of Budesonide; BAFF: B Cell Activating Factor; APRIL: A Proliferation-inducing Ligand; MMF: Mycophenolate Mofetil; BP: blood pressure.