Uncomplicated Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in 2 Other Patients with Metformin Accumulation

Dear Editor,

we recently described 3 patients treated with continuous renal replacement therapy (CRRT) for acute kidney injury with metformin accumulation and severe metabolic acidosis [1]. Metformin accumulation partly inhibits mitochondrial metabolism in the liver and other tissues [2‒4], so it could also impair (mitochondrial) citrate clearance. Patients described in our series received regional citrate anticoagulation (RCA) without signs of citrate accumulation, such as a ratio of total to ionized plasma calcium concentration >2.5 or a high strong ion gap metabolic acidosis.

Soon after the publication of that case series, we treated 2 other patients with inadvertent metformin accumulation with CRRT and RCA. One was admitted to the ASST Grande Ospedale Metropolitano Niguarda in Milan, Italy, as the previous ones. The other patient was admitted to the IRCCS Humanitas Research Hospital in Milan, Italy. Written informed consent was obtained from both patients for the publication of this report.

The first patient (male, 73 years old) presented with acute kidney injury due to an obstructing bladder clot developed following a prostate biopsy. His arterial pH was 7.00, PCO₂ 21 mm Hg, bicarbonate 5 mmol/L, base excess −24 mmol/L, lactate 15 mmol/L. Creatinine was 8 mg/dL and urea 233 mg/dL, with anuria. The metformin serum concentration before CRRT initiation was 37 μg/mL (therapeutic drug level is <2 μg/mL). The central venous oxygen saturation (ScvO₂) was 68% with a hemoglobin of 5.6 mg/dL, and the core body temperature was 34°C.

The second patient (male, 77 years old) had acute kidney injury due to a urinary tract infection with dehydration. Two months earlier, his home therapy was changed to ertugliflozin-sitagliptin and metformin. His arterial pH was 6.93, PCO₂ 11 mm Hg, bicarbonate 2 mmol/L, base excess −28 mmol/L, lactate 14 mmol/L. Creatinine was 17 mg/dL, and urea was 269 mg/dL. Of note, urinary output was 200 mL/h, with glycosuria. SvO₂ was 86% and core body temperature was 34.4°C. The metformin serum concentration was 42 μg/mL.

These 2 patients likely suffered from “metformin-associated lactic acidosis” [5]. Their condition was mainly caused by metformin accumulation, which inhibited mitochondrial metabolism, as indicated by hypothermia and relatively high ScvO₂ [2‒4]. Anemia and infection may have also played a minor role.

Patients were treated with CRRT with RCA, using diluted citrate (Regiocit 18/0, Baxter Healthcare Corporation, Deerfield, IL, USA) with a target citrate concentration of 3 mmol/L for 48 h. Similarly, to the cases presented previously [1], no signs of citrate accumulation were observed (Fig. 1). All acid-base variables, including serum lactate concentration, progressively normalized. Both patients were discharged alive from the hospital.

In conclusion, these additional data corroborate our previous findings, supporting the safety of using diluted citrate during CRRT treatment in patients with metformin accumulation. A certain degree of residual citrate metabolism and/or rapid recovery of mitochondrial function due to effective blood purification could be the putative mechanistic explanation of our findings. Close monitoring for signs of citrate accumulation remains extremely important.