By Jasmine Nee and Martin Fried, MD
Peer Reviewed
LEARNING OBJECTIVES
1. What is metformin-associated lactic acidosis?
2. How does severe acidemia lead to acute kidney injury?
3. How do you treat metformin-associated lactic acidosis?
CASE SUMMARY
The patient is a 40-year-old man with alcohol dependence and type II diabetes who presented to the emergency department for alcohol intoxication. After arriving hemodynamically stable with reassuring labs, he become tachypneic, confused, and lethargic a few hours later. At this point, he admitted that he took “a few” metformin pills in a suicide attempt. Arterial blood gas was significant for a pH < 6.8 and a lactate > 22 mg/dL. Due to this decompensation, he was intubated, admitted to the medical ICU, and started on hemodialysis via a newly-placed hemodialysis catheter. He was later transitioned to continuous veno-venous hemofiltration, after which his lactic acidosis resolved. Upon stopping hemodialysis, however, the patient’s creatinine continued to steadily rise, so he was transferred to general medicine for further management.
On arrival to general medicine, an initial urinalysis showed hematuria with red blood cells and granular casts but no red blood cell casts. Given the unclear diagnosis, a renal biopsy was done demonstrating acute tubular necrosis overlying mesangial IgA deposition, consistent with acute kidney injury in the setting of newly diagnosed IgA nephropathy. Acute tubular necrosis was thought to be the result of acidemia-induced hypotension. The patient’s creatinine levels continued to downtrend steadily and he was discharged home with plans for renal and psychiatric follow-up.
DISCUSSION
1. What is metformin-associated lactic acidosis?
Metformin, an antihyperglycemic biguanide, is a commonly used diabetic medication that increases glucose utilization by promoting insulin binding to insulin receptors in the liver. Normally, metformin is filtered at the glomerulus and excreted in the urine in its unmetabolized form.1 At the correct dose, metformin does not significantly alter insulin concentrations and rarely leads to hypoglycemia. However, in a subset of patients, metformin can accumulate to dangerous levels and lead to metformin-associated lactic acidosis (MALA). Patients at increased risk for MALA include those who are dehydrated due to vomiting or poor oral intake and those with heart failure, respiratory failure, alcohol abuse, liver failure, or a history of chronic kidney disease (CKD).[1,2] Patients can also present with MALA after intentionally overdosing on metformin in a suicide attempt.
In general, lactic acidosis can be classified into two categories based on etiology. Type A lactic acidosis results from poor tissue perfusion secondary to shock, whereas type B lactic acidosis results from lactic acid accumulation secondary to specific medications (eg, biguanides, salicylates, isoniazid, albuterol) or cancers (eg, lymphoma, leukemia).[3] One important caveat is septic shock, one of the most common causes of shock, which often starts out as a type A lactic acidosis due to hypoperfusion but can persist as a type B process due to altered oxidative phosphorylation. At excessive concentrations, metformin leads to type B lactic acidosis via 2 mechanisms. Firstly, metformin inhibits mitochondrial respiratory chain complex I, limiting oxidative respiration and citric acid cycle activity. This consequently blocks hepatic gluconeogenesis, propels a shift from aerobic to anaerobic metabolism, and promotes a build-up of lactic acid and its substrates. [4] Lactic acidosis, in this case, should be viewed as a response to severely low levels of energy generation. Secondly, metformin promotes the conversion of glucose to lactate in the splanchnic bed of the small intestine. [5]
In terms of notable lab values, an initial arterial blood gas in patients with MALA will often show a profoundly low pH (ie, < 7.0), low bicarbonate level (ie, < 10 mEq/L), and elevated lactate level (ie, > 20 mg/dL). Excessive lactate, especially in the presence of CKD, can produce an unusually high anion gap. Patients may also have marked leukocytosis with bandemia.
2. How does severe acidemia lead to acute kidney injury?
Traditionally, metabolic acidosis is thought to be a consequence of kidney failure. However, in situations like MALA, acidemia itself can be the culprit of acute kidney injury. Broadly speaking, severe acidemia damages multiple organ systems with neurological, skin, cardiac, renal, gastrointestinal, and hematological manifestations. Among these, acute kidney injury results from 2 primary processes: (1) renal hypoperfusion and (2) a direct reduction in eGFR that is independent of renal perfusion.
The first process stems from the cardiac effects of severe acidemia. Patients with MALA can enter a state of shock, developing hypothermia and hypotension, within 3 hours of presentation. Clinically, patients will demonstrate signs of respiratory distress, such as hyperventilation with Kussmaul breathing, a mechanism of respiratory compensation for severe metabolic acidosis. Hypotension results from vasodilation, poor cardiac contractility, and a catecholamine surge that leads to arrhythmia and reduced cardiac output.[6] The shocked state reduces perfusion of the kidneys and leads to prerenal acute kidney injury.
The second process is based on the idea that the presence of a non-renal acidosis, such as lactic acidosis or respiratory acidosis, can aggravate retention of organic anions and suppress production of bicarbonate in the renal tubules. In cases of severe acidemia, renal regulatory mechanisms dedicated to correcting the acid-base imbalance can ironically intensify metabolic acidosis, promote interstitial fibrosis, and exacerbate existing chronic kidney disease.[7] Although the details of this response are still unclear, proposed theories include endothelin-mediated tubulo-interstitial injury and persistent activation of the renin-angiotensin system.[7]
The 2 processes mentioned above have distinct pathophysiologies, but they can be thought of as key components in a vicious cycle of worsening renal function and metabolic acidosis. Acute kidney injury secondary to acidemia can further worsen lactic acidosis, which in turn contributes to prerenal acute kidney injury.
3. How do you treat metformin-associated lactic acidosis?
Currently, the recommended treatment for MALA is limited to supportive measures, such as administering active charcoal following an acute ingestion of metformin and securing the patient’s airway, breathing, and circulation. For acidosis with a pH < 7.10, patients may receive an infusion of sodium bicarbonate, although this practice remains controversial.[8] Other supportive therapies include norepinephrine administration for hypotension and warm fluids and blankets for hypothermia. If additional cardiac support is warranted, patients may also receive vasopressin.[9]
More controversial in the treatment of MALA is the use of hemodialysis, which is largely reserved for patients with profound acidosis, existing renal disease, or a comorbid critical illness. Hemodialysis has been demonstrated to effectively correct metformin-associated acid-base disturbances and clear metformin more effectively. Approximately 85% of patients are able to return to a normal therapeutic level of metformin with a total of 15 hours of hemodialysis.[10] However, prolonged treatment promotes intracellular accumulation of metformin. Once hemodialysis ends, redistribution may lead to an unwanted rebound in serum metformin concentrations.[11] Given this post-hemodialysis risk, it is important to consider transitioning patients who are hemodynamically stable to continuous renal replacement therapy (CRRT) or intermittent hemodialysis for protective management, as was seen in our patient.[9,12]
SUMMARY
MALA is one of the most dangerous side effects of metformin that can lead to severe renal failure with an alarming estimated mortality rate of 25–50%.1,13 At normal therapeutic levels, metformin functions to reduce hepatic glucose production and increase insulin sensitivity. However, at excessive concentrations, metformin can induce severe acidemia through type B lactic acidosis. Thus, any patient with type II diabetes on metformin presenting with a markedly elevated metabolic anion gap and a high lactate level should be strongly considered for MALA. Regardless of the etiology of acidosis, severe acidemia adversely affects multiple organ systems and impairs response to native and exogenous catecholamines, which need to be kept in consideration during treatment. Current treatment for MALA centers on supportive measures for patients in respiratory distress or shock and therapies to reduce the serum lactate and metformin concentrations, which can include hemodialysis and CRRT. With all of this in mind, careful consideration should be given before prescribing or administering metformin to patients carrying risk factors for MALA, most notably moderate-to-severe renal impairment, cardiac or respiratory insufficiency, a history of lactic acidosis, severe infection or poor tissue perfusion, and abnormal hepatic function.
Dr. Jasmine Nee, is a third year medical student at NYU School of Medicine
Dr. Martin Fried is a chief medical resident at NYU Langone Health
Peer reviewed by Kevin Felner, MD, Associate Professor, Division of Pulmonary/Critical Care, Department of Medicine, NYU Langone Health
Image courtesy of Wikimedia Commos
References
1. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism. 2016;65(2):20-29. doi:10.1016/j.metabol.2015.10.014 https://www.ncbi.nlm.nih.gov/pubmed/26773926
2. Lalau J. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Safety. 2010;33(9):727-740. doi:10.2165/11536790-000000000-00000
3. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med. 1992;20(1):80-93. doi:10.1097/00003246-199201000-00020 https://www.ncbi.nlm.nih.gov/pubmed/1309494
4. Visconti L, Cernaro V, Ferrara D, et al. Metformin-related lactic acidosis: is it a myth or an underestimated reality? Renal Failure. 2016;38(9):1560-1565. doi:10.1080/0886022x.2016.1216723
5. Bailey C, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Brit J Pharmacol. 1992;105(4):1009-1013. doi:10.1111/j.1476-5381.1992.tb09093.x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908709/
6. Kimmoun A, Novy E, Auchet T, et al. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. Crit Care. 2015;19(1). doi:10.1186/s13054-015-0896-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391479/
7. Kovesdy CP. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD? Nephrol Dial Transpl. 2012;27(8):3056-3062. doi:10.1093/ndt/gfs291 https://www.ncbi.nlm.nih.gov/pubmed/22851628
8. Finkle SN. Should dialysis be offered in all cases of metformin-associated lactic acidosis? Crit Care. 2009;13(1):110. doi:10.1186/cc7161
9. Lam N, Sekhon G, House AA. Metformin-associated lactic acidosis following intentional overdose successfully treated with tris-hydroxymethyl aminomethane and renal replacement therapy. Case Rep Nephrol. 2012;2012:1-5. doi:10.1155/2012/671595
10. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med. 2009;37(7):2191-2196. doi:10.1097/ccm.0b013e3181a02490
11. Regolisti G, Antoniotti R, Fani F, et al. Treatment of metformin intoxication complicated by lactic acidosis and acute kidney injury: the role of prolonged intermittent hemodialysis. Am J Kidney Dis. 2017. doi:10.1053/j.ajkd.2016.12.010
12. Keller G, Cour M, Hernu R, et al. Management of metformin-associated lactic acidosis by continuous renal replacement therapy. PLoS One. 2011;6(8):E23200. doi:10.1371/journal.pone.0023200
13. Kajbaf F, Lalau JD. Mortality rate in so-called “metformin-associated lactic acidosis”: a review of the data since the 1960s. Pharmacoepidem Dr S. 2014;23(11):1123-1127. doi:10.1002/pds.3689