Cutting-edge markers | BAFF and APRIL: What is the clinical exploration value of "source indicators" in the pathogenesis of IgA nephropathy?

The clues to the cause of IgA nephropathy (IgAN) may be hidden in two names——BAFF and APRIL. As B cell activating factor (BAFF) and proliferation-inducing ligand (APRIL), they are the "upstream throttle" that drives the abnormal production of pathogenic IgA. Understanding their roles in IgAN is a key to understanding IgA nephropathy.

In recent years, targeted drugs targeting the BAFF/APRIL axis have gradually entered clinical vision (such as dual-target strategies that simultaneously inhibit BAFF and APRIL, and APRIL single-target antibodies), which has confirmed the important position of this axis in the pathology and intervention of IgAN. So, what role do BAFF and APRIL play in IgA nephropathy, and what is their clinical exploration value?

BAFF and APRIL: the “upstream throttle” for abnormal production of pathogenic IgA

BAFF (B cell activating factor) and APRIL (proliferation-inducing ligand) belong to the tumor necrosis factor (TNF) superfamily and are key cytokines that regulate B cell survival, proliferation, immunoglobulin class switching, and plasma cell differentiation. In IgA nephropathy, the two happen to be the "upstream throttle" for the abnormal production of pathogenic IgA.

More and more observational studies suggest that serum BAFF and APRIL levels in IgAN patients are significantly higher than those in healthy people, and they are closely related to disease activity and risk of progression [1–5]:

^{Serum BAFF is elevated and correlates with disease severity:Studies have shown that serum/plasma BAFF in IgAN patients is higher than that in healthy controls, and is positively correlated with renal function, proteinuria, and pathological damage. The study by ZHENG et al. (n=76) measured plasma BAFF levels and found that it was positively correlated with serum creatinine, proteinuria, uric acid, and the degree of renal tubular atrophy/interstitial fibrosis [1]; the study by XIN et al. included 153 IgAN patients, 55 healthy controls, and 20 disease controls, tested serum BAFF levels, and found that serum BAFF levels in IgAN patients were significantly higher than those in controls [2].
APRIL and disease progression:APRIL (TNFSF13) is involved in IgAN progression and its levels correlate with renal function indicators. The study by HAN et al. (44 cases of IgAN, 23 healthy controls, and 8 cases of non-IgAN glomerulopathy) showed that APRIL was significantly related to serum creatinine (P=0.04) and eGFR (P=0.008), and suggested that APRIL is involved in the progression of IgAN [4].
APRIL works with Gd-IgA1 and BAFF:A single-center longitudinal observational study by Gopal et al. (n=38) found that APRIL levels were significantly positively correlated with Gd-IgA1 (r=0.556, P=0.003) and positively correlated with BAFF levels (r=0.657, P<0.001); patients with proliferative pathological changes such as crescents, mesangial hyperplasia, and endothelial hyperplasia had higher APRIL and BAFF levels [5].}

BAFF and APRIL provide mechanism-level clues for understanding "where the disease comes from" and exploring "whether to intervene and whether the intervention is in place." They are not only a window to understand the mechanism of IgAN, but also a bridge connecting mechanism and clinical exploration.

How do they cause disease? ——The core promoter in "Four Strikes"

To understand the value of BAFF/APRIL testing, one must first understand their role in the pathogenesis of IgAN. The currently recognized disease framework is the "four hits" theory:

• First strike: Gd-IgA1 overproduction.Galactose-deficient IgA1 (Gd-IgA1) is mainly produced in plasma cells of the intestinal and nasopharyngeal mucosa. APRIL and BAFF are the core cytokines driving this process—they promote mucosal B cell survival, IgA class switching, and differentiation of Gd-IgA1-producing plasma cells. It can be said that the rise of BAFF/APRIL is the fuel that ignited the "first hit".
• Second hit: Anti-Gd-IgA1 autoantibody formation.The exposed N-acetylgalactosamine (GalNAc) neoantigen is recognized by IgG/IgA, producing autoantibodies.
• The third hit: Pathogenic immune complex formation。Gd-IgA1 binds to autoantibodies and accumulates in the blood due to impaired liver clearance.
• The fourth hit: mesangial zone deposition and kidney damage.The complex is deposited in the glomerular mesangium, activates complement (C3, C5b-9, etc.), triggers inflammation, mesangial hyperplasia, and fibrosis, and ultimately leads to progressive decline in renal function.

Among the two, APRIL is more critical for the production of Gd-IgA1, while BAFF is more involved in B cell survival and expansion. The two work together to form a pathogenic closed loop. Simultaneously inhibiting both pathways can suppress Gd-IgA1 more completely than single-point blockade. This also explains from the mechanism why interventions targeting this axis have attracted much attention in research.

Future direction: From "empirical medication" to "marker-driven"

The 2025 KDIGO update has included APRIL inhibitors, BAFF/APRIL dual-target inhibitors and complement inhibitors into recommended intervention strategies for the entire population; the "Chinese Clinical Practice Guidelines for Adult IgA Nephropathy (2025)" also proposed the concept of "staged treatment" for the first time - the induction of remission stage directly targets the production of pathogenic IgA, and the maintenance stage uses long-term control in a safe and effective way, with the goal of "annual eGFR decline rate < 1 ml/min/1.73m²".

As pointed out in multiple medical reviews: Although there are existing drugs that act on different links such as mucosal immunity, BAFF/APRIL axis, complement and hemodynamics, there is still a lack of reliable molecular markers in clinical practice to determine "which pathway is dominant in a certain patient", making it difficult to guide the precise selection and combination of drugs.

BAFF/APRIL is an important candidate to fill this gap. They are both "mechanical markers" (reflecting whether the B cell axis is over-activated) and "pharmacodynamic markers" (reflecting whether targeted drugs achieve target inhibition). When detection and treatment form a closed loop——

Measure BAFF/APRIL → Determine B cell axis activity → Evaluate whether to intervene on this axis → Retest during intervention to evaluate target inhibition and efficacy → Dynamically adjust.

This is the important development direction of IgAN towards "biomarker-driven precision medicine". At the same time, dynamic monitoring methods such as urine markers and multi-omics are also developing rapidly, and it is expected to realize real-time and non-invasive tracking of disease activity and renal function in the future.

Conclusion

The complexity of IgA nephropathy lies in the fact that it is not driven by a single pathway, but is the result of multiple intertwined links. In this network, BAFF and APRIL are in the "source" position - they ignite the abnormal production of pathogenic IgA, and thus become an important window for observing diseases and exploring personalized intervention.

Incorporating BAFF/APRIL into clinical research and exploratory testing of IgA nephropathy will help promote the transition from "empirical judgment" to "mechanical decision-making" and from "post-intervention evaluation" to "during-intervention monitoring." On the BAFF/APRIL axis, mechanisms, markers and clinical practices are being connected into a tighter closed loop.

References:

[1] Zheng N, Fan J, Wang B, et al. Expression profile of BAFF in peripheral blood from patients of IgA nephropathy: Correlation with clinical features and Streptococcus pyogenes infection. Mol Med Rep. 2017;15(4):1925-1935. doi:10.3892/mmr.2017.6190.

[2] Xin G, Shi W, Xu LX, Su Y, Yan LJ, Li KS. Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. J Nephrol. 2013;26(6):683-690. doi:10.5301/jn.5000218.

[3] High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients. Nephrol Dial Transplant. 2021;36(9):1765. doi:10.1093/ndt/gfaa344.

[4] Han SS, Yang SH, Choi M, et al. The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy. J Am Soc Nephrol. 2016;27(11):3430-3439. doi:10.1681/ASN.2015060677.

[5] Anjana G, Noble G. Clinicopathological correlation of APRIL and BAFF in IgA nephropathy — A single center longitudinal observational study. Nephrol Dial Transplant. 2021;36(Suppl 1):gfab104.0030. doi:10.1093/ndt/gfab104.0030.

*Statement

"This article is academic/industry information popularization. It does not constitute diagnosis and treatment advice and does not replace in-person diagnosis by a practicing physician."