APRIL- and BAFF/APRIL-targeted therapies for IgA nephropathy: meta-analysis of placebo-controlled trials

Phase 3 interim reports have expanded the evidence for therapies targeting a proliferation-inducing ligand (APRIL) alone or both B-cell activating factor (BAFF) and APRIL in IgA nephropathy (IgAN). We evaluated their effects relative to placebo on proteinuria, kidney function, pharmacodynamic biomarkers, and safety. We searched PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to May 14, 2026. Double-blind, parallel-group randomized controlled trials enrolling adults with biopsy-confirmed primary IgAN were included. Random-effects meta-analyses synthesized within-trial treatment effects relative to placebo. Trial-level estimates were presented with the corresponding drug, target-class subgroup analyses were performed as secondary exploratory analyses, and certainty of evidence was assessed using GRADE. Seven randomized controlled trials were included, of which five contributed to the 24-hour urinary protein-to-creatinine ratio (UPCR) synthesis. The pooled placebo-relative ratio of means (RoM) for 24-hour UPCR was 0.52 (95% confidence interval [CI], 0.46–0.59). A secondary analysis limited to telitacicept datasets also showed a reduction in 24-hour UPE (RoM, 0.50; 95% CI, 0.32–0.79). Short-term eGFR change from baseline favored active treatment (mean difference, 5.68 mL/min/1.73 m²; 95% CI, 3.94–7.41), although mature phase 3 eGFR slope data were unavailable. Active treatment also reduced Gd-IgA1, IgA, IgG, and IgM. Any infection was numerically more frequent with active treatment (RR, 1.15; 95% CI, 0.97–1.35), whereas serious infections were rare and imprecisely estimated (RR, 0.31; 95% CI, 0.08–1.21). The included trials support reductions in 24-hour UPCR with APRIL- and BAFF/APRIL-targeted therapies relative to placebo. Comparative efficacy and safety between drugs or target classes remain uncertain, as do durable kidney benefit and long-term immune safety. PROSPERO, CRD420261337013. The pooled evidence from placebo-controlled trials supported a reduction in 24-hour UPCR with the evaluated APRIL- and BAFF/APRIL-targeted therapies. Any infection was numerically more frequent with active treatment, whereas serious infections were rare and imprecisely estimated; longer-term immune safety remains to be defined. Placebo-relative treatment effects showed broadly similar directions across target-class subgroups, with variation in effect magnitude among trials.