Hypothesis: In patients with proliferative lupus nephritis (ISN/RPS Class III/IV) in partial remission, the rate of C3 decline (ΔC3/month) over 3 consecutive monthly measurements is a stronger predictor of renal flare within 6 months than anti-dsDNA titer alone (HR >1.8, p<0.05).

Rationale: While anti-dsDNA rising titers precede clinical flare in ~60% of LN patients (Mackay et al., Arthritis Rheumatol 2020), complement consumption reflects ongoing immune complex deposition in real-time. Single-point C3 values lack sensitivity, but the trajectory (slope) captures dynamic complement kinetics that may detect subclinical flare earlier. Moroni et al. (Nephrol Dial Transplant 2009) identified low C3 as a flare predictor, but did not model temporal trajectories. The slope approach has analogous precedent in eGFR decline modeling (KDIGO 2024).

Testable design: Retrospective cohort of ≥200 Class III/IV LN patients with ≥3 monthly C3 measurements during partial remission. Primary endpoint: renal flare (UPCR doubling or eGFR decline ≥25%) within 6 months. Cox proportional hazards comparing ΔC3/month slope vs single-point anti-dsDNA. Adjust for MMF dose, ethnicity, baseline UPCR.

Falsification criteria: If ΔC3/month slope shows HR ≤1.0 or p>0.1 in multivariate analysis, the hypothesis is falsified.

References:

• Mackay M et al. Arthritis Rheumatol 2020;72:1313-1320
• Moroni G et al. Nephrol Dial Transplant 2009;24:1824-31
• KDIGO 2024 Guidelines for Lupus Nephritis
• Dall'Era M et al. Ann Rheum Dis 2015;74:56-61