We report here on a case of MALA due to metformin accumulation in a diabetic patient with AKI on CKD, focusing on relevant pharmacokinetic issues that should guide the choice of the most appropriate modality of emergency renal replacement therapy (RRT).
Clinical history and laboratory data
A 76-year-old man with type 2 diabetes, CKD (usual serum creatinine [sCr] concentration 1.8 mg/dL, eGFR 36 mL/min/1.73 m2) and ischemic cardiomyopathy presented with a 48-hour history of vomiting, abdominal pain, hypotension and oliguria after uncomplicated day-surgery for inguinal hernia three days earlier. His usual medications included aspirin 100 mg, ramipril 7.5 mg, bisoprolol 2.5 mg, furosemide 25 mg bid, metformin 1000 mg tid, glimepiride 1 mg. Physical examination revealed an oliguric 72 Kg man in moderate respiratory distress, with cold extremities and a large hematoma of the abdominal wall (7 x 6 cm on CT scan, extending to the scrotum and left thigh). Blood pressure was 90/50 mmHg while on dopamine 8 mg/Kg/min, pulse rate 56 beats/min, respirations 32 breaths/min, peripheral oxygen saturation 98% on 50% O2, tympanic temperature 35.5° C. Initial laboratory workup showed a severe anion gap (AG) metabolic acidosis with hyperlactatemia and AKI on CKD (Fig.1). Other routine serum values and urine toxicology tests were unremarkable. RRT was started with an AK 200ultra machine (Gambro/Baxter, Mirandola, Italy) and a 1.8 m2 polysulfone F8 HPS filter (Fresenius, Palazzo Pignano, Italy). A 16-hour sustained low-efficiency dialysis (SLED) session with regional citrate anticoagulation was planned (blood flow rate 200 mL/min, bicarbonate [32 mmol/L] dialysis fluid rate 300 mL/min, countercurrent flow direction, body weight change + 2.5 Kg). Blood samples were collected during the SLED session, and metformin levels were measured subsequently by high-performance liquid chromatography-tandem mass spectrometry. Metformin levels (therapeutic values 1-3 mg/L) at SLED start were in the lethal range, and decreased rapidly within 8 hours of treatment; however, a moderate rebound in serum metformin levels was observed 4 hours after the end of SLED (Fig.2). Acid-base parameters at the end of SLED returned to normal range (Fig.1). Urinary output rapidly increased during 48 hours since the end of SLED, thus no further dialysis was required.
Anti-hyperglycemic effect of metformin relies mainly on a decreased endogenous glucose production via decreased hepatic gluconeogenesis through inhibition of mitochondrial glycerophosphate dehydrogenase As a result, the conversion of lactate to pyruvate and glucose is impaired and lactate production is also accelerated. Metformin clearance is reduced proportionally to the decrease in kidney function, and the drug accumulates in erythrocytes and peripheral tissues with multiple-dose oral administration. While registered metformin labeling still reports formal contraindication in diabetic patients with serum creatinine >1.5 mg/dL in men or >1.4 mg/dL in women or abnormal creatinine clearance, the updated US Food and Drug Administration, the European Renal Best Practice, the 2012 Kidney Diseases Initiative and Global Outcomes and the National Institute for Health and Care Excellence guidelines allow metformin treatment down to eGFR 30 mL/min/1.73 m2 . However, all of these guidelines call for a review of drug dose in patients with eGFR <60 mL/min/1.73m2, and recommend caution in patients with eGFR <45 mL/min/1.73 m2 and potentially unstable kidney function. Serum metformin concentration can be measured by liquid chromatography/tandem mass spectrometry, yet available only at specialized institutions. Thus, if metformin intoxication is probable, appropriate treatment should be immediately started, while diagnosis can only be confirmed subsequently. In our patient daily metformin dose (3 g/day) was clearly inappropriate for his known eGFR. Furthermore, hypovolemic shock due to a large hematoma complicating surgery may have precipitated oliguric AKI, and conceivably facilitated metformin accumulation in the intracellular compartment. As RRT allows drug removal and acid-base status correction at the same time, it is the most efficient treatment of severe metformin intoxication. However, the optimal RRT modality in the case of metformin intoxication/overdose is not established. Since both severe acidemia and the direct toxic effect of metformin are associated with hemodynamic instability, ideally one should choose those RRT techniques combining efficient drug clearance and hemodynamic tolerability, and possibly reducing the rebound phenomenon.
In fact, given metformin accumulation in peripheral tissues, a significant rebound in its plasma concentration is likely after a 4-h session of standard IHD. Thus, prolonged diffusive techniques may be better suited to cope with long-term metformin redistribution from the deep compartment. Prolonged intermittent modalities, such as SLED, may be regarded as the best compromise, as they allow similar hemodynamic stability together with higher efficiency in the unit of time (urea clearance 80 mL/min vs 20-30 mL/min) compared to CRRT. Yet, clinical experience with SLED in metformin intoxication is anecdotal, and no direct drug measurements have been reported. In this patient, notwithstanding a 16-h SLED session, we still observed a moderate rebound in plasma metformin concentration after the end of RRT. In conclusion, in patients with CKD stage 3a and 3b metformin daily dose should be appropriately reduced, and kidney function closely monitored. Patients with possible metformin intoxication and AKI should be started promptly on prolonged (16 hours or longer) RRT modalities aimed at drug clearance and acid-base status correction, also minimizing the rebound phenomenon. A practical approach for the management of suspect metformin intoxication is depicted in Fig.3.
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