Systemic Citrate Toxicity During Regional Citrate Anticoagulation for Continuous Kidney Replacement Therapy

Regional citrate anticoagulation (RCA) is the preferred anticoagulation strategy for continuous kidney replacement therapy (CKRT) because it prolongs circuit lifespan while reducing bleeding complications compared with systemic heparin. Although generally safe, systemic citrate accumulation remains the principal metabolic complication of RCA and occurs when citrate delivery exceeds the combined metabolic and extracorporeal capacity for citrate elimination. This narrative review summarizes current evidence regarding citrate metabolism, the pathophysiological mechanisms of citrate accumulation, associated risk factors, biochemical diagnosis, monitoring strategies, and therapeutic management. Citrate metabolism depends predominantly on mitochondrial oxidative capacity rather than hepatic function alone, making circulatory shock and impaired tissue perfusion the principal determinants of citrate intolerance, whereas isolated liver dysfunction is often well tolerated. Systemic citrate accumulation is characterized by a distinctive biochemical profile including ionized hypocalcemia, an increased total-to-ionized calcium ratio, escalating calcium infusion requirements, high anion-gap metabolic acidosis, and frequently hyperlactatemia, while overt clinical manifestations usually occur late. Consequently, early recognition relies on structured biochemical monitoring and interpretation of serial trends rather than isolated measurements. Management should focus on restoring the balance between citrate delivery and citrate elimination by reducing citrate exposure when appropriate, optimizing extracorporeal citrate removal, correcting metabolic abnormalities, and improving tissue perfusion. Contemporary RCA practice should therefore emphasize individualized physiological assessment and integrated biochemical monitoring to facilitate early recognition, prevent progression to overt toxicity, and preserve the well-established safety and efficacy of RCA.