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

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. 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. 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. 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. CRD42024582600