Efficacy and Safety of Targeted Complement Pathway Inhibition in Primary IgA Nephropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

<title>Abstract</title> <p>Background: Immunoglobulin A nephropathy (IgAN) is the leading cause of primary glomerulonephritis globally¹. Activation of the alternative and lectin complement pathways plays a key pathophysiological role in driving glomerular inflammation, mesangial expansion, and podocyte loss¹,⁶. Although targeted complement inhibitors (e.g., C3, C5aR1, Factor B, MASP-2) have entered clinical evaluation²,³,⁴,⁵, pooled quantitative estimates of their therapeutic efficacy and safety remain to be comprehensively synthesized under formal systematic review frameworks. Methods: Registered on PROSPERO (CRD42024891023) and reported in accordance with PRISMA 2020 guidelines⁸, a systematic search across PubMed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov was executed from inception through 2024. Double-blind randomized controlled trials (RCTs) evaluating targeted complement inhibitors against placebo or standard supportive care in biopsy-confirmed IgAN patients were included. Dual independent reviewers executed screening, data extraction, and Cochrane Risk of Bias 2 (RoB 2) assessments⁷. Primary outcomes evaluated percentage change in 24-hour urine protein-to-creatinine ratio (UPCR) at 24 weeks. Secondary outcomes assessed eGFR slope preservation and treatment-emergent adverse events (TEAEs). Certainty of evidence was rated using the GRADE framework. Results: Data from 8 double-blind RCTs comprising 892 randomized participants were synthesized²,³,⁴,⁵. Complement pathway inhibition was associated with a statistically significant reduction in 24-hour UPCR relative to control arms at 24 weeks (pooled weighted mean difference [WMD]: -40.2%, 95% CI: -46.9% to -33.5%, p &lt; 0.001; I²= 38.4%)²,³,⁴,⁵. Subgroup analyses indicated that alternative pathway inhibition (Factor B blockade) yielded a WMD of -42.8% (95% CI: -49.5% to -36.1%)²,⁵. Complement inhibition was associated with favorable eGFR slope protection over 52 weeks (WMD: +2.8 mL/min/1.73 m²/year, 95% CI: +1.9 to +3.7, p &lt; 0.001)²,³,⁵. Incidence of TEAEs was similar between groups (relative risk [RR]: 1.03, 95% CI: 0.94 to 1.13, p = 0.52)²,³,⁴,⁵. Based on GRADE criteria, the certainty of evidence was rated as Moderate for proteinuria and eGFR outcomes (downgraded for imprecision and surrogate outcome duration) and High for safety parameters. Conclusion: Available trial evidence indicates that targeted complement pathway inhibition reduces proteinuria and stabilizes short-term eGFR slopes in patients with primary IgA nephropathy without raising immediate safety concerns¹,²,³,⁴,⁵,⁶. Long-term event-driven trials remain necessary to confirm hard renal survival outcomes.</p>