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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2015  |  Volume : 26  |  Issue : 2  |  Page : 325-328
Metformin-associated lactic acidosis in a peritoneal dialysis patient


Al Hada Armed Forces Hospital, Al Hada, Taif, Saudi Arabia

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Date of Web Publication3-Mar-2015
 

   Abstract 

Metformin is one of the commonly used drugs in type-2 diabetes mellitus. It reduces glucose levels by increasing insulin sensitivity, reducing hepatic glucose release and increasing muscle uptake. One of the serious complications associated with metformin use is lactic acidosis, and it is associated with high morbidity and mortality. This is more likely to happen in patients with renal failure due to reduced clearance. International guidelines recommend discontinuing metformin in advanced renal failure. We report a case of metformin-associated lactic acidosis in a patient with end-stage renal disease on peritoneal dialysis. The patient presented with severe lactic acidosis, which was successfully treated with hemodialysis.

How to cite this article:
Almaleki N, Ashraf M, Hussein MM, Mohiuddin SA. Metformin-associated lactic acidosis in a peritoneal dialysis patient. Saudi J Kidney Dis Transpl 2015;26:325-8

How to cite this URL:
Almaleki N, Ashraf M, Hussein MM, Mohiuddin SA. Metformin-associated lactic acidosis in a peritoneal dialysis patient. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Jan 17];26:325-8. Available from: http://www.sjkdt.org/text.asp?2015/26/2/325/152498

   Introduction Top


Metformin is a commonly used oral anti-diabetic agent in the treatment of type-2 diabetes mellitus (DM). A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes recommends metformin therapy as first-line treatment along with lifestyle modification to treat type-2 DM. Metformin is the only anti-diabetic medicine that has been shown to prevent the cardiovascular complications of diabetes. It helps reduce LDL cholesterol and triglyceride levels, and is not associated with weight gain. When prescribed appropriately, metformin is associated with few side-effects (predominantly gastro-intestinal) and has a low risk of hypoglycemia. Lactic acidosis is a rare but potentially life-threatening complication of metformin. The overall mortality of lactic acidosis is approximately 50%. Current international guidelines recommend stopping the use of metformin in advanced renal fai-lure. [1],[2],[3],[4],[5],[6],[7],[8] It is unusual for any patients on peritoneal dialysis (PD) to be taking metformin. We hereby report a case of metformin-associated lactic acidosis in a patient on PD and review the literature regarding previous reports of metformin-associated lactic acidosis in PD patients and modes of treatment used to treat this complication.


   Case Report Top


An 83-year-old man with a background history of DM, ischemic heart disease recent left below-knee amputation for diabetic foot and end-stage renal disease on PD for 3.5 years presented with nausea, recurrent vomiting and loss of appetite for one week. The family also reported that the patient had been experiencing repeated episodes of hypotension on PD. There were no other systemic complaints. His medication included aspirin, alfa calcidol, erythropoietin, ranitidine and sevelamer hydrochloride. His PD regimen included 10 L 1.36% Dianeal exchanges over 8 h at night with no day time exchanges. His most recent adequacy test showed KT/V 1.4, creatinine clearance (CrCl) 36 L/week and ultrafiltration 900 mL/ day. He had been anuric for the last few months. Given his old age and poor quality of life, it was decided to continue with PD despite low clearance.

The family also mentioned that one week before admission, he experienced an episode of hypoglycemia and that they had switched his insulin to metformin without seeking any medical advice. Metformin was borrowed from a family member.

On examination, he was fully conscious and oriented. Rest of the examination revealed a pulse rate of 97/min with a regular rhythm. His blood pressure was 145/62 mm Hg and oxygen saturation was 98% on room air. He was afebrile with no significant cardiovascular and chest findings. There was evidence of below left knee amputation with a non-infected stump. Clinically, there was no evidence of sepsis or dehydration and his PD effluent was clear, with a white cell count of 7/mm 3 . His random blood sugar was 7.8 mmol/L. His other investigations showed sodium 138 mmol/L, potassium 4.8 mmol/L, bicarbonate (HCO 3 ) 6 mmol/L, chloride 97 mmol/L, white blood cell count 14.9/μL and hemoglobin 9.8 g/dL. His liver function test, including prothrombin time, was normal. His initial blood gas showed severe high anion gap (AG) metabolic acidosis [Table 1]. Anion gap was 35 with a base excess (BE) -22. Initial ECG and chest X-ray were unremarkable. His serial arterial blood gas analysis is shown in [Table 1].
Table 1: Serial acid–base parameters and serum lactate levels.

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A diagnosis of metformin-associated lactic acidosis was made. He was admitted to a high dependency unit and was started on IV bicarbonate infusion, while PD was temporarily stopped. The patient was also started on insulin and metformin was stopped. Arterial blood gas improved in terms of pH; however, the lactate level was persistently very high. It was decided to treat the patient with hemodialysis (HD) to remove metformin and correct lactic acido-sis. The patient received four sessions of HD spanning a total of 15 h. After each session, the lactate level improved, but started to rise again, consistent with the large volume of distribution of metformin [Figure 1]. After the 4 th session, the lactate level stayed below 2. His metformin level was extremely elevated at 2020 mg/L (0.16-1). On discharge, the patient was converted back to PD and was given clear advice to avoid use of metformin in the future.
Figure 1: Serum lactate levels in relation to hemodialysis (HD) sessions.

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   Discussion Top


Biguanides, including phenformin and metformin, became available as anti-hyperglycemic agents in the 1950s. They reduce insulin resistance, decrease hepatic glucose output and increase muscle uptake of glucose. [1] The major toxicity associated with biguanides is lactic acidosis. The high rate of lactic acidosis led to withdrawal of phenformin in the 1970s, and metformin is the only biguanide available in most countries.

Metformin has negligible plasma protein binding, with a large volume of distribution ranging from 63-276 L. It is excreted unmetabolized in urine and its plasma half-life in patients with normal kidney function is approximately 5 h. However, its half-life may increase by two- to three-times in patients with renal failure. [2],[3]

Metformin-associated lactic acidosis is rare, and its incidence in a systematic review was 5.1 cases per 100,000 patient-years. The mechanism of metformin-associated lactic acidosis includes conversion of glucose to lactate in the splanchnic bed and inhibition of hepatic gluconeogenesis from lactate, pyruvate and alanine. [4],[5] Significant lactic acidosis occurs only in the presence of comorbid conditions including renal failure, hepatic failure, heart failure, hypoxic state, dehydration or hemodynamic instability. There was no evidence of any of these comorbid conditions other than renal failure in our patient.

A mortality rate of 45% and 48% has been reported in patients with metformin-associated lactic acidosis in two case series. The median plasma concentration in one series was 20.3 mg/L in patients who survived compared with 6.3 mg/L in patients who died. [6],[7] In our patient, the plasma metformin level was much higher (2020 mg/L). This could potentially be explained by complete loss of native kidney function in our patient. The National Institute for Health and Care Excellence (NICE) guidelines (UK) recommend reviewing the dose of metformin if the serum creatinine exceeds 130 μmol/L or the estimated glomerular filtration rate (eGFR) is below 45 mL/min/1.73 m 2 . NICE also recommend stopping metformin if the serum creatinine exceeds 150 μmol/L or the eGFR is below 30 mL/min/1.73 m 2 . [8]

To the best of our knowledge, there are only three case reports in the literature of metformin-associated lactic acidosis in a patient already on PD. In the first report, the patient was managed using PD with a bicarbonate buffer and bicarbonate infusion. This patient's acidosis remained refractory to treatment and she died. According to the authors, the option of HD or continuous renal replacement was not considered due to comorbidities. [9] In the second report, the patient experienced long-lasting neurological squeals despite surviving the episode of lactic acidosis. He was treated with bicarbonate therapy and bicarbonate-based HD. [10] In the third report, the patient was accidentally prescribed metformin and was successfully managed with HD. [11]

Although it is not clear whether metformin is removed by PD, metformin's large volume of distribution probably prevents its adequate removal by PD. Whether PD itself can compound the lactic acidosis because of its lactate-based buffer is not known. Lactate is absorbed at 25 mEq/h during PD and there is a possibility that it could worsen lactic acidosis. However, patients on PD do not develop lactic acidosis in the absence of an associated comorbidity causing lactic acidosis. [12] HD, on the other hand, has been shown to reduce the concentration of metformin and lactate. However, the large volume of distribution and potentially long half-life in the setting of renal failure mean that complete HD removal of metformin may take days because of the large tissue distribution and rebound. [13],[14]

Continuous veno-venous hemofiltration has also been used, but metformin clearance is generally less than conventional HD. [15],[16] Acetate buffer-based PD was successfully employed in two patients with metformin-associated lactic acidosis. However, acetate-based PD solutions have gone out of favor due to the risk of encapsulating peritoneal sclerosis and loss of ultrafiltration. [17],[18] Therefore, our patient was not considered for acetate-based buffer in the long run.

Conflict of interest: None declared.

 
   References Top

1.
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.  Back to cited text no. 1
    
2.
Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf 1999;20:489-503.  Back to cited text no. 2
    
3.
Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81-98.  Back to cited text no. 3
    
4.
Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992;105:1009-13.  Back to cited text no. 4
    
5.
Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: Mechanism of action and tolerability. Pharmacol Res 1994;30:187-228.  Back to cited text no. 5
    
6.
Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999;20:377-84.  Back to cited text no. 6
    
7.
Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: A prognostic and therapeutic study. Crit Care Med 2009;37:2191-6.  Back to cited text no. 7
    
8.
NICE clinical guideline 87. May 2009.  Back to cited text no. 8
    
9.
Khan IH, Catto G, Macleod A. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ 1993;307: 1056-7.  Back to cited text no. 9
    
10.
Lim PS, Huang CC, Wei JS. Metformin-induced lactic acidosis: Report of a case. J Formos Med Assoc 1992;91:374-6.  Back to cited text no. 10
    
11.
Schmidt R, Horn E, Richards J, Stamatakis M. Survival after metformin-associated lactic acdosis in peritoneal dialysis--dependent renal failure. Am J Med 1997;102:486-8.  Back to cited text no. 11
    
12.
Dixon SR, McKean WI, Pryor JE, Irvine RO. Changes in acid-base balance during peritoneal dialysis with fluid containing lactate ions. Clin Sci 1970;39:51-60.  Back to cited text no. 12
    
13.
Sambol NC, Chiang J, Lin ET, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol Ther 1995;35:1094-102.  Back to cited text no. 13
    
14.
Sitori CR, Franceschini G, Galli-Kienle M, et al. Disposition of metformin (N,N dimethylbiguanide) in man. Clin Pharmacol Ther 1978;24:683-93.  Back to cited text no. 14
    
15.
Teale KF, Devine A, Stewart H, Harper NJ. The management of metformin overdose. Anaesthesia 1998;53:698-701.  Back to cited text no. 15
    
16.
Lalau JD, Andrejak M, Morinière P, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: A study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989;27:285-8.  Back to cited text no. 16
    
17.
Hayat JC. The treatment of lactic acidosis in diabetic patient by peritoneal dialysis using sodium acetate. A report of two cases. Diabetologia 1974; 10(5):485-7.  Back to cited text no. 17
    
18.
Faller B, Marichal JF. Loss of ultrafiltration in CAPD: A role for acetate. Perit Dial Bull 1984;4:10-3.  Back to cited text no. 18
    

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Correspondence Address:
Dr. Syed A Mohiuddin
Al Hada Armed Forces Hospital, P. O. Box 1347 Zip Code 21944, Al Hada, Taif
Saudi Arabia
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DOI: 10.4103/1319-2442.152498

PMID: 25758883

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