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

Background: Regional citrate anticoagulation (RCA) is the recommended anticoagulation strategy for continuous kidney replacement therapy (CKRT) because it prolongs circuit lifespan and reduces bleeding risk compared with systemic heparin. However, systemic citrate accumulation may occur when citrate delivery exceeds metabolic or extracorporeal clearance, potentially leading to severe metabolic disturbances. Summary: Citrate is normally metabolized through mitochondrial oxidative pathways in the liver, skeletal muscle, and kidneys, generating bicarbonate and releasing bound calcium. Conditions associated with impaired oxidative metabolism—most notably circulatory shock, but also severe hypoperfusion, hyperlactatemia, hypothermia, or excessive citrate load—predispose to systemic citrate accumulation. Severe hepatic dysfunction alone is rarely sufficient in the absence of circulatory failure. Citrate accumulation produces a characteristic biochemical profile including ionized hypocalcemia, elevated total calcium, an increased total-to-ionized calcium ratio, high anion-gap metabolic acidosis, ionized hypomagnesemia, and hypernatremia. Clinical manifestations typically occur late and include hypotension, arrhythmias, neuromuscular irritability, and progressive metabolic acidosis. Early recognition relies on structured biochemical monitoring rather than clinical signs alone. Key Messages: Systemic citrate toxicity reflects impaired mitochondrial oxidative metabolism and reduced systemic metabolic reserve rather than isolated hepatic dysfunction. Circulatory shock is the principal risk factor. Early biochemical surveillance allows timely intervention and renders citrate accumulation largely reversible. When applied within protocolized monitoring strategies, RCA remains a safe and effective anticoagulation method for CKRT.