Redefining the Future of Autoimmune Kidney Disease: The Central Role of BAFF and APRIL

By Marshall Fordyce, M.D, Founder and Chief Executive Officer, Vera Therapeutics, Inc. 

At Vera Therapeutics, we began our journey with a single, driving question: what truly causes autoimmune kidney diseases like IgA nephropathy (IgAN), and how can we intervene at the source? As the most common glomerulonephritis worldwide, IgAN affects adults in the prime of their lives, with the average age of diagnosis around 35.¹Historically, the standard of care for this chronic, progressive disease—which leads to kidney failure in at least 50% of patients—has focused on managing general aspects of chronic kidney disease while leaving the root cause largely unaddressed.^2,3

Our search identified two cytokines, BAFF and APRIL, as the engine behind B-cell activity. Convinced that inhibiting both was the key to changing the course of this disease, we scoured the field for a rationally designed molecule that could do exactly that. That search—and our unwavering belief in the science—led us to our lead product candidate.

Targeting the Root Cause: Dual BAFF/APRIL Inhibition

IgAN is fundamentally a B-cell–driven autoimmune condition that leads to kidney pathology and can ultimately result in complete loss of organ function.² In these patients, B cells produce both the autoantigen and the autoantibody that form immune complexes, which deposit in the kidney’s glomeruli and trigger inflammation and progressive scarring.⁴

BAFF and APRIL are critical to this process. These two cytokines both drive B-cell activity by binding to transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a receptor on the surface of B cells.⁴ In patients with IgAN, BAFF and APRIL signal B cells to produce galactose-deficient immunoglobulin A1 (Gd-IgA1), an abnormal form of the IgA antibody that the immune system mistakenly targets as foreign.⁴ As an autoantigen, Gd-IgA1 triggers B-cell production of anti-Gd-IgA1 autoantibodies.⁴ Both the autoantigen and autoantibody cluster into immune complexes, which deposit in the glomeruli and cause inflammation and progressive kidney damage.⁴ Over time, IgAN can cause blood in the urine (hematuria), excess protein in the urine (proteinuria), and, ultimately, irreversible loss of kidney function.⁴

Mounting evidence suggests that dual inhibition of both BAFF and APRIL may offer a promising approach to alter the course of disease.⁴ Both cytokines have key roles in activating B cells to produce the components of immune complexes. Through dual inhibition, we may be able to more fully address the pathophysiology of the disease.⁴ This strategy of targeting the disease at its source aligns directly with a key treatment goal outlined in the 2025 Kidney Disease Improving Global Outcomes (KDIGO) guidelines for the management of IgAN: preventing or reducing immune complex formation and the subsequent glomerular inflammation.⁵ By targeting both pathways, there is potential to reduce the production of Gd-IgA1 and its autoantibodies, hematuria, and proteinuria, and ultimately slow the decline in kidney function.⁴ With dual BAFF/APRIL inhibition, and selecting a carefully studied dose, we’re taking aim at the immune drivers of IgAN in a way that could represent a paradigm shift in science.

Advancing Science, Expanding Impact

Our work in dual BAFF/APRIL inhibition reflects the future of immunology-driven therapeutics: rational design, precise targeting, and a focus on true disease modification. Our lead candidate is designed to modulate these pathways with the aim of fundamentally changing how IgAN is treated.

What excites me most is not just the scientific progress, but the major impact it could have on real people. I’ve spoken with patients and families who have spent years living with uncertainty, facing the threat of kidney failure requiring dialysis or transplantation. For decades, people with IgAN had limited options. By focusing on the underlying pathophysiology, we hope to give patients and families the possibility of living free from the burdens and uncertainty that have defined these diagnoses for too long. I believe there is real cause for optimism—and it goes beyond IgAN. The lessons we’re learning with dual BAFF/APRIL inhibition—about targeting the upstream source of disease—are already shaping how we think about other autoimmune kidney diseases, and potentially beyond.

Our goal is bold yet simple: to help people living with autoimmune kidney diseases live longer, healthier lives. This work is urgent, and it’s possible. I invite you to learn more about our approach, our team, and our mission at https://veratx.com.

References:

1. _{^{Jarrick S, Lundberg S, Welander A, et al. Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study. J Am Soc Nephrol. 2019;30(5):866-876. doi:10.1681/ASN.2018101017}}
2. _{^{Kwon CS, Daniele P, Forsythe A, Ngai C. A Systematic Literature Review of the Epidemiology, Health-Related Quality of Life Impact, and Economic Burden of Immunoglobulin A Nephropathy. J Health Econ Outcomes Res. 2021;8(2):36-45. Published 2021 Sep 1. doi:10.36469/001c.26129}}
3. _{^{Pitcher D, Braddon F, Hendry B, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-738. doi:10.2215/CJN.0000000000000135}}
4. _{^{Cheung CK, Barratt J, Liew A, Zhang H, Tesar V, Lafayette R. The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies. Front Nephrol. 2024;3:1346769. Published 2024 Feb 1. doi:10.3389/fneph.2023.1346769}}
5. _{^{Kidney Disease: Improving Global Outcomes (KDIGO) IgAN and IgAV Work Group, Rovin BH, Barratt J, et al. KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). Kidney Int. 2025;108(4S):S1-S71. doi:10.1016/j.kint.2025.04.004}}
6. _{^{Huang X, Xu G. An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective. Front Pharmacol. 2021;12:715253. Published 2021 Aug 23. doi:10.3389/fphar.2021.715253}}
7. _{^{Rauen T, Eitner F, Fitzner C, et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015;373(23):2225-2236. doi:10.1056/NEJMoa1415463}}
8. _{^{Barratt J, Lafayette RA, Floege J. Therapy of IgA nephropathy: time for a paradigm change. Front Med (Lausanne). 2024;11:1461879. doi:10.3389/fmed.2024.1461879}}