What is the relationship between Metformin (Metformin hydrochloride) and Acute Kidney Injury (AKI)?

From the Guidelines

Metformin should be temporarily discontinued in patients with acute kidney injury (AKI) due to the increased risk of lactic acidosis, a rare but serious side effect, as recommended by the most recent guidelines 1. The decision to restart metformin should be made in consultation with a healthcare provider who can assess kidney function through blood tests measuring creatinine and calculating eGFR. Metformin accumulates in the setting of reduced kidney function, and this accumulation can lead to lactic acidosis by inhibiting mitochondrial function and promoting anaerobic metabolism. This risk is particularly heightened during AKI when kidney function rapidly declines. Once metformin is restarted, kidney function should be monitored regularly, with more frequent monitoring in patients with chronic kidney disease or other risk factors for AKI. Some key points to consider include:

• Metformin is generally safe to use in patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², but the dose should be reduced or withdrawn if eGFR falls below this threshold 1.
• Alternative glucose-lowering medications, such as insulin, may be necessary during the interruption of metformin therapy to maintain glycemic control.
• The risk of lactic acidosis associated with metformin use is very low in absolute terms, but it is increased in patients with reduced kidney function or those who experience acute kidney injury 1. Regular monitoring of kidney function and adjustment of the metformin dose as needed can help minimize this risk. In addition to monitoring kidney function, it is also important to monitor for other potential side effects of metformin, such as vitamin B12 deficiency, which can occur with long-term use 1. Overall, the benefits of metformin in improving glycemic control and reducing the risk of microvascular and cardiovascular complications make it a valuable medication for patients with type 2 diabetes, but its use requires careful consideration of the potential risks and regular monitoring of kidney function.

From the FDA Drug Label

5 WARNINGS AND PRECAUTIONS

1. 1 Lactic Acidosis ... Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

The use of metformin may increase the risk of lactic acidosis in patients with renal impairment, including those with Acute Kidney Injury (AKI).

• Renal impairment is a significant risk factor for metformin-associated lactic acidosis.
• The risk of metformin accumulation and lactic acidosis increases with the severity of renal impairment.
• Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m^2.
• In patients at risk for the development of renal impairment, renal function should be assessed more frequently 2.

From the Research

Metformin and Acute Kidney Injury (AKI)

• Metformin is associated with an increased risk of lactic acidosis, particularly in patients with acute kidney injury (AKI) 3, 4, 5, 6, 7
• The risk of lactic acidosis is higher in metformin users with AKI, and increases with the severity of AKI 3
• Metformin-induced lactic acidosis with AKI is a rare but potentially lethal condition that requires prompt diagnosis and treatment 4, 5
• Renal replacement therapy, such as sustained low-efficiency dialysis (SLED), is an effective treatment for metformin-associated lactic acidosis in patients with AKI 5, 6

Risk Factors for Metformin-Associated AKI

• Volume depletion due to gastrointestinal losses, such as acute gastroenteritis, is a common precipitating factor for metformin-associated AKI 7
• Previous renal dysfunction, such as mild-to-moderate chronic kidney disease (CKD), does not appear to influence the severity or outcome of metformin-associated AKI 7
• Other risk factors for AKI, such as dehydration, alcohol consumption, and the use of certain medications (e.g. angiotensin receptor blockers or SGLT2 inhibitors), may also contribute to the development of metformin-associated AKI 4

Treatment and Management

• Prompt recognition and treatment of metformin-associated lactic acidosis and AKI are crucial to prevent serious complications and improve outcomes 3, 4, 5, 6
• SLED is a rational choice for renal replacement therapy in patients with metformin-associated lactic acidosis and AKI, as it allows for effective removal of metformin and correction of metabolic acidosis 6
• A 16-h SLED session may be sufficient to reduce metformin levels to a safe range, but additional dialysis sessions may be necessary to prevent rebound in serum metformin levels 6