Advances and unmet needs in the management of proliferative lupus nephritis: evidence, guidelines, and emerging therapies.

Proliferative lupus nephritis is a major cause of kidney failure and premature mortality in patients with systemic lupus erythematosus. Although mycophenolate-based regimens and cyclophosphamide remain standard induction therapies, up to one-third of patients have refractory disease, and many fail to achieve a complete renal response, as demonstrated in the ASPREVA, AURORA, and BLISSLN trials. Treatment-related toxicity-particularly from prolonged glucocorticoid exposure-contributes to cumulative organ damage. Recent guideline updates emphasize early assessment of treatment response, glucocorticoid minimization, and the selective addition of targeted therapies. Belimumab improves composite and complete renal response rates when added to standard therapy and reduces renal events, particularly in patients with proliferative histology. Voclosporin, a novel calcineurin inhibitor with predictable pharmacokinetics, increases complete renal response rates and rapidly reduces proteinuria in patients with preserved kidney function. Despite these advances, refractory disease and relapse remain common, prompting investigation of additional therapeutic pathways. Obinutuzumab, a type II anti-CD20 monoclonal antibody, demonstrated higher complete renal response rates than placebo in a phase 3 trial, albeit with increased serious infections. Anifrolumab, which targets type I interferon signaling, has shown favorable trends in reducing proteinuria and systemic disease activity in early lupus nephritis studies and is undergoing phase 3 evaluation. Newer agents, such as iscalimab, a CD40 pathway inhibitor, have reduced proteinuria in phase 2 trials. This review summarizes the epidemiology, prognostic markers, and current and emerging therapies, and proposes a practical, response-guided framework aligned with contemporary guidelines to improve kidney outcomes while limiting toxicity.