Regional citrate anticoagulation (RCA) enables prolonged continuous kidney replacement therapy (CKRT) filter lifespan. However, membrane diffusive performance might progressively decrease and remain unnoticed. We prospectively evaluated the kinetics of solute clearance and factors associated with decreased membrane performance in 135 consecutive CKRT-RCA circuits (35 patients). We recorded baseline patients' characteristics and clinical signs of decreased membrane performance. We calculated effluent/serum ratios (ESR) as well as respective clearances for urea, creatinine and β2-microglobuline at 12, 24, 48 and 72 h after circuit initiation. Using mixed-effects logistic regression model analyses, we assessed the effect of time on those values and determined independent predictors of decreased membrane performance as defined by an ESR for urea < 0.81. We observed a minor but statistically significant decrease in both ESR and solute clearance across the duration of therapy for all three solutes. We observed decreased membrane performance in 31 (23%) circuits while clinical signs were present in 19 (14.1%). The risk of decreased membrane performance significantly increased over time: 1.8% at T1 (p = 0.16); 7.3% at T2 (p = 0.01); 15.7% at T3 (p = 0.001) and 16.4% at T4 (p < 0.003). Four factors present within 24 h of circuit initiation were independently associated with decreased membrane performance: arterial blood bicarbonate level (OR 1.50; p < 0.001), activated partial thromboplastin time (aPTT; OR = 0.93; p = 0.02), fibrinogen level (OR 6.40; p = 0.03) and Charlson score (OR 0.10; p < 0.01). COVID-19 infection was not associated with increased risk of decreased membrane performance. Regular monitoring of ESR might be appropriate in selected patients undergoing CKRT.