Can methotrexate cause impaired renal function?

From the Guidelines

Methotrexate can cause renal insufficiency, and its use should be carefully considered in patients with pre-existing renal impairment. The medication can directly affect kidney function through several mechanisms, including precipitation of methotrexate and its metabolites in the renal tubules, particularly in acidic urine, causing tubular damage 1. According to the British Association of Dermatologists' guidelines, reduction in methotrexate dosage should be considered in those with suboptimal renal function, and the medication should be avoided in patients on dialysis and with a creatinine clearance < 20 mL min-1 1. Key risk factors for methotrexate-induced kidney injury include:

• Pre-existing renal impairment
• Dehydration
• Concurrent use of other nephrotoxic medications
• Advanced age
• High-dose therapy Patients taking methotrexate should maintain adequate hydration, have regular monitoring of renal function through blood tests (creatinine, BUN), and avoid concurrent use of NSAIDs when possible. A more recent study published in 2020 by the Joint American Academy of Dermatology-National Psoriasis Foundation also emphasizes the importance of monitoring renal function in patients taking methotrexate, particularly in those with risk factors for renal insufficiency 1. Dose adjustments are necessary for patients with reduced kidney function, and in some cases, leucovorin rescue may be used to reduce toxicity after high-dose methotrexate administration. Early detection of renal impairment is crucial, as discontinuation or dose adjustment can often reverse the kidney damage if caught early. Regular laboratory monitoring, including CBC and liver function tests, should be performed every 3 to 6 months, assuming no abnormalities in laboratory test results, and periodic renal monitoring should be considered in patients with poor renal function 1.

From the FDA Drug Label

Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure.

Methotrexate can cause renal insufficiency, particularly in patients with pre-existing impaired renal function. The drug's elimination is reduced in these patients, leading to increased serum levels and a higher risk of toxicity, including renal failure. Key factors that contribute to this risk include:

• Impaired renal function
• Concurrent use of certain drugs
• Delayed methotrexate elimination It is essential to monitor patients closely for signs of renal toxicity and adjust the dosage or discontinue treatment as needed to minimize the risk of renal insufficiency 2, 2, 2.

From the Research

Methotrexate and Renal Insufficiency

• Methotrexate (MTX) has been shown to cause renal impairment, particularly at high doses 3, 4, 5, 6.
• Studies have demonstrated that high-dose MTX can lead to a decrease in glomerular filtration rate (GFR) and creatinine clearance, even in patients without signs of systemic toxicity 3.
• The risk of renal dysfunction is increased in patients with pre-existing renal insufficiency, comorbidities, or those taking concomitant nephrotoxic medications 7, 4, 6.
• Delayed elimination of high-dose MTX has been linked to renal impairment, with patients experiencing delayed MTX elimination being at higher risk of developing renal dysfunction 5.

Factors Contributing to Renal Insufficiency

• High-dose MTX administration (>1 g/m2) increases the risk of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) 4, 6.
• Patient factors, such as age (>50 years) and male sex, may also contribute to the risk of renal dysfunction 4.
• Concomitant use of nephrotoxic agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics, can exacerbate renal insufficiency 7.

Monitoring and Prevention

• Regular monitoring of serum creatinine and MTX levels is essential to detect early signs of renal dysfunction and prevent long-term damage 3, 5, 6.
• Alkaline hyperhydration, metabolic salvage with leucovorin, and close monitoring of serum MTX and creatinine concentrations can help prevent MTX-associated AKI 6.
• Glucarpidase (carboxypeptidase-G2) may be considered for patients with MTX overexposure to prevent and lessen AKI and other potential toxicities 6.