The levels of cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are increased in patients with immunoglobulin A nephropathy (IgAN), and a number of treatments targeting these cytokines are under development for IgAN. Information on this important topic was presented at the American Society of Nephrology’s Kidney Week 2023 meeting.

Following these proceedings, featured expert Carla M. Nester, MD, MSA, FASN, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Nester’s clinical perspectives on this topic are presented here.

In their sessions at Kidney Week 2023, Hitoshi Suzuki, MD, PhD, and Heather N. Reich, MD, PhD, provided insights into the roles of APRIL and BAFF in the pathogenesis of IgAN and the therapies targeting these cytokines. The average clinician is not used to hearing about the cytokines BAFF and APRIL. However, these cytokines may be important to the 4-hit hypothesis of IgAN—the leading theory on how IgAN develops. In this hypothesis, the first hit comes from B cells producing galactose-deficient IgA1 (ie, Gd-IgA1). The abnormal IgA accumulates and leads other B cells to produce autoantibodies targeting the abnormal IgA (the second hit). The interaction of these antibodies then leads to the formation of immune complexes, the third hit. The fourth hit occurs when immune complexes bind to mesangial cells in the kidney, leading to glomerular inflammation and tissue damage.

BAFF and APRIL are both cytokines that play a role in B-cell survival and proliferation. As Gd-IgA1 and the immunoglobulins they form complexes with are produced by B cells, presumably under the stimulation of BAFF and APRIL in their usual B-cell role, interfering with the function of these 2 cytokines has the potential to play a role in the development of IgAN. There is interest in whether blocking these cytokines may limit the production of Gd-IgA1 and the associated autoantibodies (Hits 1 and 2), reducing the risk for deposition of immune complexes and subsequent glomerular inflammation.

Regardless of whether they are involved in the first or second hit, it could be quite useful to block BAFF and/or APRIL to either prevent the production of Gd-IgA1 or reduce the production of immune complexes and the resulting glomerular inflammation and tissue damage. I think that this is a very reasonable approach in the setting of a disease such as IgAN where there is an abnormal B-cell product, in this case Gd-IgA1.