APRIL: A Key Factor in the Pathogenesis of IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide, affecting approximately 2.5 per 100,000 individuals (1). Until recently, guidelines primarily focused on supportive care (2). IgAN has multifactorial pathogenesis and occurs due to a complex interplay of environmental factors like exposure to mucosal antigens and genetic susceptibility. These factors lead to a dysfunctional mucosal immune response, producing galactose-deficient IgA1 (Gd-IgA1) and the downstream cascade referred to as the 4-hit hypothesis (Figure 1). However, the 4-hit hypothesis does not explain all aspects of IgAN pathogenesis; for example, 16% of healthy individuals showed deposited glomerular IgA without any signs of kidney diseases (3). Gd-IgA1 is also found in healthy subjects, indicating that additional abnormalities must take place before the disease develops (4). Regardless of these underlying mechanisms, B cells are thought to play an important role in the pathogenesis. Two B cell growth factors, a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF), have overlapping but distinct roles in the initiation of IgAN through promotion of B cell activation and generation of Gd-IgA1 (5).

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Role of APRIL in the pathogenesis of IgAN—the tonsil- and gut-kidney axis

Citation: Kidney News 16, 1

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Under physiological conditions, APRIL, BAFF, and their receptors have specific roles in B cell maturation and survival (Figure 2). BAFF binds to three receptors: 1) the BAFF receptor; 2) the B cell maturation antigen (BCMA); and 3) the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) to regulate earlier stages of B cell homeostasis, development, and maturation of primary B cells. APRIL binds strongly to BCMA and with lower affinity to TACI to modulate the function of later stages of B cell and plasma cell maturation and survival in bone marrow and mucosa. APRIL also binds cell surface proteoglycans, which may increase localized APRIL concentration and signaling. APRIL and BAFF also have independent roles in B cell Ig isotype class-switching (5).

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Roles of APRIL and BAFF in the normal physiology of B cell maturation and survival

Citation: Kidney News 16, 1

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Disruption of B cell tolerance is one potential mechanism underlying the role of APRIL in immune-related conditions. Through its function in IgA class-switching and survival of IgA-producing plasma cells, APRIL has a key role in the pathophysiology of IgAN. Elevated APRIL levels result in increased production of Gd-IgA1, providing a critical link to hit 1 of the 4-hit hypothesis (Figure 1) (5–7). Increased APRIL and Gd-IgA1 levels have been linked to IgAN disease severity and progression to kidney failure, whereas the relevance of elevated BAFF levels in IgAN are less well established (5). IgAN recurrence post-transplant is preceded by an increase in serum APRIL levels. In alignment with these clinical observations, genome-wide association studies have identified APRIL as a key susceptibility locus for IgAN (5).

Two anti-APRIL agents (sibeprenlimab [NCT05248646] and zigakibart [NCT05852938]) are in phase 3 clinical development, and three TACI fusion protein antagonists (povetacicept [NCT05732402], atacicept [NCT04716231], and telitacicept [NCT05799287]), which bind and inhibit both APRIL and BAFF, are in phases 1/2 (povetacicept) and 3 (atacicept and telitacicept) (6, 8). Sibeprenlimab, a humanized IgG2 monoclonal antibody that blocks APRIL, demonstrated significant reduction in proteinuria and stabilization of the estimated glomerular filtration rate compared with placebo at 12 months in a phase 2 study of 155 patients with IgAN, with an acceptable safety and tolerability profile. Complete suppression of APRIL and an approximate 65% reduction in pathogenic Gd-IgA1 levels were observed with sibeprenlimab (9). Patients receiving sibeprenlimab had a preserved serologic response to the mRNA COVID-19 vaccination (10), and the COVID-19 infection rate was higher in the placebo cohort at the end of the trial (9). In addition, a phase 1/2, open-label study of zigakibart showed a clinically meaningful and sustained reduction in proteinuria through 12 months (11). The safety of dual APRIL and BAFF inhibitors needs to be established in larger studies, given the important role played by these cytokines in B cell survival (12).

In conclusion, APRIL and BAFF are key factors in B cell biology and IgAN pathogenesis (5, 7). Preliminary clinical data show promise for APRIL as an important therapeutic target. As for all immunomodulatory therapies, studies will need to be vigilant in monitoring and assessing the risk: benefit profile of these exciting, new treatments.