Efficacy and safety of supportive and immunosuppressive therapies in the treatment of lgA nephropathy: a network Meta-analysis of randomized clinical trials.

BACKGROUND: IgA nephropathy has a poor prognosis. This network meta-analysis aims to evaluate the efficacy and safety of all currently available drugs comprehensively and systematically for the treatment of IgA nephropathy. METHODS: We searched MEDLINE, EMBASE, Cochrane Library until Nov 15, 2024. Primary outcomes were 24-hour proteinuria and UPCR; secondary included ESRD, doubling serum creatinine (SCr), and adverse events (AEs). Bayesian analysis provided RRs and SUCRA rankings. RESULTS: Analyzing 37 RCTs (4889 patients) with 15 interventions: For reducing 24-hour proteinuria, AZA+CTX ranked highest (SUCRA 95.8%), superior to systemic corticosteroids (45.2%), other immunosuppressants (CsA 82.1%, MMF 72.1%, AZA 43.9%, CTX 21.0%), BAFF/APRIL inhibitors (63.6%), HCQ (62.9%), and RASi (16.4%). For UPCR reduction, BAFF/APRIL inhibitors (91.3%) and ERA (74.2%) outperformed systemic corticosteroids (46.8%), other immunosuppressants (MMF 74.0%, AZA+CTX 68.2%, TAC 43.8%), and TRF-budesonide (65.5%). Regarding renal protection, LEF (doubling SCr: 92.6%; ESRD: 79.1%) and systemic corticosteroids (doubling SCr: 77.0%; ESRD: 72.6%) were effective for both endpoints. For ESRD risk reduction, SGLT2i ranked second (77.0%), followed by TRF-budesonide (58.4%), with AZA+CTX being least favorable (5.5%). Safety analysis showed higher AE/SAE risks with CTX/AZA+CTX; TRF-budesonide had the next highest SAE ranks, though inter-group differences were non-significant. CONCLUSION: AZA+CTX was associated with an effective reduction in 24-hour proteinuria in small RCTs, but it also increased the risk of renal failure progression and had poor safety. Systemic corticosteroids and TRF-budesonide balanced proteinuria reduction with slowing renal failure, though SAE vigilance is needed. Among new agents, BAFF/APRIL inhibitors and ERA excelled at UPCR reduction with favorable safety. In supportive care, SGLT2i significantly reduced CKD progression risk while maintaining a favorable safety profile. TRIAL REGISTRATION: CRD42024582600