Targeting the BAFF and APRIL Pathway in IgA Nephropathy: From Disease Pathogenesis to Clinical Trial Evidence

This is the authors' abstract. We don't add key points for this paper.

Immunoglobulin A nephropathy (IgAN) is an immune-mediated glomerular disease driven by dysregulated mucosal B-cell immunity, leading to the overproduction of galactose-deficient IgA1 (Gd-IgA1) and the formation of immune complexes with anti–Gd-IgA1 IgG and IgA immunoglobulins. These immune complexes deposit in the renal mesangium, triggering mesangial activation, proliferation and downstream inflammatory injury. Central to this process are members of the tumor necrosis factor (TNF) superfamily, A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF). These ligands are crucial for B-cell maturation, IgA class-switch recombination, and the survival of long-lived plasma cells through their receptors: BAFF receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA). Preclinical models in IgAN demonstrate that BAFF and APRIL are important regulators of mucosal IgA responses, and their accumulation promotes autoantibody formation and downstream immune-complex mediated glomerular injury. Serum and urinary levels of BAFF and APRIL are elevated in patients with IgAN. Furthermore, APRIL and TACI are overexpressed in mucosal tissue, and their activity correlates with Gd-IgA1 levels, proteinuria, and renal histologic severity of patients with IgAN. These mechanistic insights provided the rationale for trials testing the safety and efficacy profile of BAFF and APRIL-targeted therapies. Selective APRIL inhibitors (sibeprenlimab, zigakibart) and dual BAFF-APRIL inhibitors (atacicept, povetacicept, telitacicept) reduce Gd-IgA1, hematuria, proteinuria, and prevent eGFR decline. Collectively, these findings position the BAFF and APRIL axis as a central therapeutic node in IgAN and support biomarker-guided, mechanism-based treatment strategies aimed at long-term disease modification. This review summarizes translational and clinical data on the BAFF and APRIL axis in IgAN, including evidence from recently published clinical trials.