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Metformin is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of metformin dose according to severity of estimated glomerular filtration rate and with periodic assessment of kidney function, (e. g. , periodic plasma creatinine measurement). The FDA recommends avoiding the use of metformin in more severe chronic kidney disease, below the estimated glomerular filtration rate (eGFR) cutoff of 30 mL/minute/1. 73 m2. Lactate uptake by the liver is diminished with metformin use because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given severely-impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include alcoholism (due to depletion of NAD+ stores), heart failure and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.

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