A case of metformin-associated encephalopathy in a patient undergoing maintenance hemodialysis

Abstract

Metformin is a major drug for the treatment of type 2 diabetes mellitus; however, its use is not recommended in dialysis patients due to the risk of lactic acidosis. Consequently, there are very few reports of metformin-associated lactic acidosis (MALA) or metformin-associated encephalopathy in dialysis patients. We report a case of a 67-year-old man undergoing maintenance hemodialysis who was admitted to our hospital with impaired consciousness. Blood tests revealed marked hypoglycemia (blood glucose level of 18 mg/dL) in addition to severe metabolic acidosis and lactic acidosis (pH 6.989, HCO3- 5.8 mmol/L, and lactate 10.7 mmol/L). The patient had a history of metformin use, and was diagnosed with MALA. We immediately initiated glucose correction and emergency hemodialysis. On the same day, magnetic resonance imaging (MRI) showed symmetrical swelling in the bilateral basal ganglia, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted and fluid-attenuated inversion recovery images, leading to a diagnosis of metformin-associated encephalopathy. The patient’s condition improved with frequent dialysis sessions, and subsequent MRI showed improvement in the lesions. The patient was discharged on the 17th day, after confirming recovery to the pre-admission level. The present case reinforces the recommendation that metformin should not be prescribed to patients undergoing dialysis.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13730-026-01146-x.

Introduction

Metformin is one of the primary drugs widely used in the treatment of diabetes mellitus. However, it has been known to potentially cause lactic acidosis [1]. Metformin alone rarely causes metformin-associated lactic acidosis (MALA). In most cases, it is said to be triggered as a consequence of conditions such as acute kidney injury, heart failure, or sepsis [2]. To mitigate this risk, the dosage must be adjusted according to the degree of renal impairment. It is contraindicated in patients with severe renal impairment and those undergoing dialysis [3]. Therefore, there have been extremely few case reports of metformin-associated encephalopathy (MAE) in dialysis patients. To the best of our knowledge, only four cases have been reported [4–6]. In this report, we present a case in which a dialysis patient was inadvertently administered metformin and subsequently developed MALA and MAE.

Case report

A 67-year-old Japanese man with end-stage kidney disease secondary to diabetic nephropathy due to type 2 diabetes mellitus had been undergoing maintenance hemodialysis for 4 years. He had been receiving medication for diabetes, including insulin degludec 6 units/day, luseogliflozin 2.5 mg/day, and vildagliptin 100 mg/day until five months ago. However, his condition was deemed poorly controlled, and metformin 500 mg/day was added, and the dose was increased to 750 mg/day two months ago. On the day of presentation, although it was a scheduled dialysis day, the patient did not come to the hospital, and his family found him at home with impaired consciousness and unable to move. He was brought to the hospital by emergency services.

At the time of admission, his blood pressure was 97/61 mmHg, and his level of consciousness was E3V4M6 on the Glasgow Coma Scale. He also had dysarthria and somnolence. Initial blood tests revealed marked hypoglycemia (blood glucose level of 18 mg/dL) in addition to severe metabolic acidosis and lactic acidosis (pH 6.989, PCO2 24.8mmHg, HCO3- 5.8 mmol/L, anion gap 35.2 mmol/L and lactate 10.7 mmol/L). Glycoalbumin was 19.7%. Other laboratory findings included lactate dehydrogenase 337 U/L, creatine kinase 2715 U/L, blood urea nitrogen 38.6 mg/dL, and creatinine 9.99 mg/dL (Table 1).

Table 1.

Laboratory findings at the time of admission

Laboratory data
blood gas analysis (room air)
pH	6.989
PCO2, mmHg	24.8
PO2, mmHg	98.5
HCO3-, mmol/L	5.8
Base excess, mEq/L	-24.2
Anion gap, mmol/L	35.2
Lactate, mmol/L	10.70
Complete blood cell count
White blood cells, /µL	4800
Red blood cells, × 104/µL	334
Hemoglobin, g/dL	11.0
Platelets, × 104/µL	11.9
Biochemistry
Total protein, g/dL	5.6
Albumin, g/dL	3.3
Aspartate transaminase, U/L	56
Alanine transaminase, U/L	24
Alkaline phosphatase, U/L	70
ɤ-Glutamyl transferase, U/L	9
Lactate dehydrogenase, U/L	337
Creatine kinase, U/L	2715
Blood urea nitrogen, mg/dL	38.6
Creatinine, mg/dL	9.99
Uric acid, mg/dL	4.2
Sodium, mEq/L	141
Potassium, mEq/L	3.5
Chloride, mEq/L	100
Calcium, mg/dL	9.0
Phosphate, mg/dL	6.4
Blood glucose, mg/dL	18
Glycoalbumin, %	19.7
Immunology
C-reactive protein, mg/dL	2.76

Due to the marked hypoglycemia and severe acidosis, immediate glucose correction and emergency hemodialysis were initiated. After dialysis, the pH improved to 7.288 and the lactate level decreased to 4.08 mmol/L, and the blood glucose level also normalized. However, there was no significant improvement in his level of consciousness. A head computed tomography (CT) scan showed symmetrical swelling in the basal ganglia. A head magnetic resonance imaging (MRI) showed symmetrical swelling in the bilateral basal ganglia, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted and fluid attenuated inversion recovery (FLAIR) images (Fig. 1). In addition, the diffusion-weighted imaging (DWI) revealed high signals in the same area (Fig. S1). Based on these findings, the patient was diagnosed with MAE. Magnetic resonance angiography showed no significant stenosis in the major arteries. Hemodialysis was performed again the following day, and post-dialysis blood gas analysis showed further improvement, with a pH of 7.409 and a lactate level of 1.64 mmol/L. Subsequently, the patient returned to his regular dialysis schedule. His level of consciousness gradually improved, and an MRI on the 16th day of hospitalization showed improvement in the lesions in the basal ganglia. Eventually, he recovered to his pre-admission condition and was discharged.

Fig. 1.

Magnetic resonance imaging (MRI) findings. Imaging at the time of admission revealed swelling of the bilateral basal ganglia (A T1-weighted; B T2-weighted image; C FLAIR). Improvement can be observed in the imaging on day 16 of hospitalization (D T1-weighted; E T2-weighted; F FLAIR)

Discussion

In this case, metformin was administered to a dialysis patient, resulting in severe lactic acidosis and metabolic acidosis. The patient’s condition improved with frequent dialysis, and he was fortunately discharged without any sequelae.

There have been previous reports of adverse events due to metformin administration in patients with renal impairment. MALA is very rare, with an estimated incidence of less than 10 cases per 100,000 person-years in one review [1]. Furthermore, because metformin is contraindicated in patients with severe renal impairment and end-stage renal disease, reports in dialysis patients are even rarer. As far as we have been able to determine, there have been four reported cases of MAE in hemodialysis patients, and all of them were discharged without any sequelae (Table 2) [4–6]. In the five cases including the present one, the duration of administration varied considerably, making it difficult to identify any clear association. Regarding dosage, based on the four previously reported cases, a metformin dose of 750 mg/day appears less likely to induce MAE; however, when the present case is taken into account, 500 mg/day might be considered within a safer range. Nevertheless, since metformin is contraindicated in dialysis patients in the first place, it is difficult to verify this point.

Table 2.

Case reports of MAE in dialysis patients

Study	Age (years old)/Sex	Metformin dose (mg)	Period of use	pH	Lactate (mmol/L)	Neurological symptoms	MRI image	Outcomes
Simon SP.et.al	63/M	Not Available	Not Available	7.28	7.1	Speech disorder Gait disturbance	swelling of the bilateral basal ganglia	Improvement without sequelae
Kang et al. (Case 1)	55/F	1000	25 days	Not Available	Not Available	Speech disorder Myoclonus	swelling of the bilateral basal ganglia	Improvement without sequelae
Kang et al. (Case 2)	62/M	1000	5 weeks	Not Available	Not Available	Speech disorder Gait disturbance Myoclonus	swelling of the bilateral basal ganglia	Improvement without sequelae
Jung et al.	51/M	850	3 months	Within the reference range	Within the reference range	Speech disorder Gait disturbance Myoclonus	swelling of the bilateral basal ganglia	Improvement without sequelae
Present case	67/M	500→750	3→2 months	6.989	10.7	Speech disorder Gait disturbance Somnolence	swelling of the bilateral basal ganglia	Improvement without sequelae

MAE may be considered to lie on a continuum with MALA. Previous reports have suggested that metformin tends to accumulate more readily in the brain than in the bloodstream [7]. Therefore, in cases of systemic metformin accumulation leading to MALA, additional accumulation within the brain may result in the development of MAE. This tendency may be further exacerbated in patients with renal impairment, including those on dialysis, as in the present case. In addition, this patient had been treated with an SGLT2 inhibitor despite being on dialysis. SGLT2 inhibitors are known to potentially induce ketoacidosis. Although reports remain limited due to the relatively recent introduction of these agents, we identified only one case report describing the concomitant occurrence of MALA and SGLT2 inhibitor–associated ketoacidosis [8]. However, in the present case, the presence of ketones could not be confirmed due to anuria. Moreover, the patient exhibited hypoglycemia rather than euglycemia, and the clinical condition improved with treatment directed at MALA without the use of insulin. These findings suggest that the contribution of the SGLT2 inhibitor to the pathophysiology in this case was likely limited.

Although the mortality rate of MALA is generally reported to range from 30% to 50%, the available case reports—including the present case—suggest that both the survival and neurological outcomes of MAE occurring in patients undergoing dialysis are comparatively favorable. One possible explanation is that metformin has a very small molecular weight, extremely low protein binding, and a moderate volume of distribution, making it readily removable by dialysis. Therefore, in patients receiving regular dialysis, the plasma concentration is presumably less likely to rise compared with non-dialysis patients. However, regarding measurement of plasma metformin levels, although higher concentrations are often associated with more severe cases, MALA has also been observed even at low concentrations, and thus its clinical utility is considered limited [1]. Clinically, for the diagnosis and assessment of the severity of MALA, evaluation with pH and lactate levels is preferred over measurement of plasma metformin concentration [9]. In addition, MALA is defined as pH < 7.35 and blood lactate > 5 mmol/L [10]. According to one report, extracorporeal therapy should be continued until the lactate level falls below 3 mmol/L and the pH exceeds 7.35 [11]. Intermittent hemodialysis is also reported to have a higher metformin clearance compared to continuous hemofiltration [12]. In the present case, the patient was already receiving maintenance dialysis, and therefore intermittent hemodialysis was performed daily until the aforementioned criteria were met, resulting in a favorable outcome.

In this case, MRI revealed swelling of the bilateral basal ganglia. Conditions that can cause such changes include, among acute diseases, toxic disorders such as carbon monoxide or methanol poisoning; metabolic disorders such as hypoglycemia or hyperglycemia; and vascular disorders such as cerebral infarction or hypertensive emergency. Among chronic conditions, differential diagnoses include toxic disorders such as toluene poisoning, metabolic disorders such as Wilson’s disease, and other diseases such as Creutzfeldt-Jakob disease [13]. In this case, hypoglycemia was also present; however, hypoglycemic encephalopathy typically shows symmetrical, faint lesions extending from the frontal white matter to the posterior limb of the internal capsule, which differs from the imaging findings in the present case. Particularly on DWI, unlike hypoglycemic encephalopathy, the lesions have well-defined margins, indicating that the changes are attributable to MAE. Based on these differences, MAE was considered more likely than hypoglycemic encephalopathy.

In conclusion, we reported a case of metformin-associated encephalopathy in a dialysis patient who was prescribed metformin. Metformin should not be prescribed to patients undergoing dialysis, and early recognition of MALA/MAE with prompt hemodialysis is essential for favorable outcomes.

Supplementary Information

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Funding

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Declarations

Conflict of interest

All authors have nothing to disclose.

Informed consent

Informed consent for publication was obtained from the patient.