The safety of regional citrate anticoagulation in renal replacement therapy

Dear Sir,

We read with interest the paper by Borg et al. ¹ evaluating the safety of regional citrate anticoagulation (RCA) in patients requiring continuous renal replacement therapy (CRRT) and their concern about citrate accumulation and toxicity in patients with liver dysfunction.

Despite post-filter infusion of calcium, citrate enters the systemic circulation and is metabolised to bicarbonate via the Krebs cycle. There is a risk that this pathway is impaired in liver dysfunction, with subsequent citrate accumulation, a reduction in ionised calcium and a high total:ionised calcium ratio, requiring escalating calcium doses to maintain normocalcaemia.

The risk however may be lower than perceived, less than 3% in some studies,^2,3 and lactic acidosis from anaerobic cellular respiration may be a more important indicator of impaired citrate metabolism than liver dysfunction per se. ³

Our local results also suggest that the risk of citrate toxicity may be very low. We have been using RCA since 2013. Sixty-three patients have received RCA for CRRT in the past 18 months, a total of 349 days. Two hundred and seventy-two calcium ratio calculations were made. Using a bilirubin concentration of less than 2 mg/dl, between 2 and 7 mg/dl, and greater than 7 mg/dl to differentiate no, mild, and severe liver dysfunction, as done in a previous study, ³ 45 patients had no liver dysfunction, 14 had mild, and 4 had severe liver dysfunction. The same Prismaflex System, Baxter protocol was used in all patients. In only one patient (1.6%) was the total to ionised calcium ratio greater than 2.4. This patient had multi-organ dysfunction syndrome from sepsis with decompensated fulminant hepatic failure, with a peak bilirubin concentration of 36.9 mg/dl and a lactataemia of 6.0 mmol/l. A threshold of 2.5 is often used as an indication of citrate toxicity; a threshold of 2.4 has a specificity of 99.2% ⁴ for mortality, suggesting that citrate toxicity below this level is very rare. It also has a sensitivity of only 55.6%, ⁴ and in our patient, other indirect features of citrate toxicity (reducing ionised calcium levels, escalating calcium compensation requirements, and significant acid–base disturbance) were not present, making the diagnosis of citrate toxicity uncertain.

Our results support the hypothesis that RCA is generally safe, and that citrate toxicity is rare, even in patients with severe liver dysfunction. We consider lactataemia a more significant risk factor for toxicity than liver dysfunction.