Ravulizumab in IgA Nephropathy

We read with great interest the article by Lafayette et al.1 titled “Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial,” published in JASN. The trial evaluated ravulizumab, a C5 complement inhibitor, in 66 patients with IgA nephropathy at 38 sites across 11 countries. This study demonstrates that a significant 30.1% relative reduction in proteinuria at 26 weeks, with sustained effects at 50 weeks, and a trend toward stabilization of eGFR were observed with ravulizumab. In addition, ravulizumab was well tolerated, with an adverse event profile similar to that for placebo. However, several limitations should be considered. First, the exclusion of patients with baseline BP ≥140/90 mm Hg, while a significant proportion of patients had hypertension according to Table 1. Moreover, the study lacks detailed information on baseline or post-treatment BP levels and changes during the trial. Given that BP control is essential in managing proteinuria,2 it is unclear whether BP reductions contributed to the observed decrease in proteinuria. Second, the relatively high baseline eGFR of participants (mean 74 ml/min per 1.73 m2) limits the generalizability of the findings to patients with moderate to severe CKD, as it is uncertain whether these patients would experience similar benefits with ravulizumab. In addition, the higher mean baseline eGFR in the ravulizumab group compared with the placebo group may have influenced the observed eGFR trajectories, potentially affecting the interpretation of the results. Third, the limited use of sodium-glucose cotransporter 2 inhibitors (21% in the ravulizumab versus 17% in the placebo groups) may obscure any potential synergistic or antagonistic effects. Given their established renoprotective benefits in reducing proteinuria,3,4 it remains unclear whether broader use of sodium-glucose cotransporter 2 inhibitors would lead to similar outcomes. Finally, while meningococcal vaccination within 3 years prior of randomization was an important safety measure, it may limit generalizability, particularly for populations without access to the vaccine or with contraindications. For nonvaccinated participants, prophylactic antibiotics were used for at least 2 weeks, which could have confounded results by influencing both the immune response to the vaccine and the outcomes of ravulizumab. These findings provide valuable insights into the potential of complement inhibition as a therapeutic strategy for IgA nephropathy. We look forward to phase 3 trial results to further confirm the efficacy and safety of ravulizumab in this patient population.