Can methotrexate (MTX) cause Acute Kidney Injury (AKI)?

From the Guidelines

Methotrexate can cause acute kidney injury (AKI), particularly at high doses, due to its potential to precipitate in the renal tubules and cause crystal nephropathy. This medication, commonly used to treat autoimmune conditions like rheumatoid arthritis and certain cancers, can directly damage the kidneys. According to a study published in Kidney International 1, methotrexate is listed as one of the common anticancer drugs associated with AKI, with crystalline nephropathy and acute tubular injury being the renal histopathologic features.

Risk Factors and Prevention Strategies

Risk factors for methotrexate-induced AKI include:

• High-dose therapy (typically doses above 500 mg/m²)
• Dehydration
• Acidic urine
• Pre-existing kidney disease
• Concurrent use of other nephrotoxic medications Prevention strategies include:
• Aggressive hydration
• Urine alkalinization (typically with sodium bicarbonate)
• Leucovorin rescue therapy when high doses are used
• Monitoring kidney function before and during methotrexate therapy, especially with high-dose regimens

Monitoring and Management

Monitoring kidney function is essential to detect early signs of AKI, such as rising creatinine levels. If AKI develops, temporary discontinuation of methotrexate and supportive care are typically recommended until kidney function recovers. A study published in the British Journal of Dermatology 1 recommends reducing the methotrexate dosage in patients with suboptimal renal function and avoiding its use in patients on dialysis or with a creatinine clearance < 20 mL min-1. Another study published in the Journal of the American Academy of Dermatology 1 emphasizes the importance of periodic renal monitoring in patients with poor renal function.

Clinical Considerations

In clinical practice, it is crucial to weigh the benefits of methotrexate therapy against the potential risks of AKI, particularly in patients with pre-existing kidney disease or other risk factors. By carefully monitoring kidney function and adjusting the methotrexate dose accordingly, healthcare providers can minimize the risk of AKI and ensure the safe use of this medication.

From the FDA Drug Label

Methotrexate may cause renal damage that may lead to acute renal failure High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure.

Methotrexate can cause Acute Kidney Injury (AKI), as it may lead to renal damage and acute renal failure, especially at high doses.

• Nephrotoxicity is a primary concern, and close monitoring of renal function is essential to prevent AKI.
• Adequate hydration and urine alkalinization are crucial to minimize the risk of renal damage.
• Measurement of serum methotrexate and creatinine levels is necessary to ensure safe administration of methotrexate 2, 2.

From the Research

Methotrexate and Acute Kidney Injury (AKI)

• Methotrexate can cause AKI, especially when administered at high doses (≥ 500 mg/m2) 3, 4, 5, 6, 7.
• The incidence of methotrexate-induced AKI varies from 2% to 12% of patients 3.
• Risk factors for methotrexate-associated AKI include:
  • History of renal dysfunction 3
  • Volume depletion 3
  • Acidic urine 3
  • Drug interactions 3
  • Male sex 7
  • Use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) 7
  • Use of diuretics with urinary acidification, such as loop diuretics 7
  • Elevated lactate dehydrogenase (LDH) levels (> 380 units/L) 6
  • Low albumin levels (< 3.6 g/dL) 6
• Mechanisms of methotrexate-induced AKI include:
  • Crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity 3, 4
  • Overexposure to methotrexate, leading to higher risk of extrakidney toxicities, morbidity, and mortality 4
• Prevention and treatment of methotrexate-induced AKI include:
  • Alkaline hyperhydration 4
  • Withdrawal of all nephrotoxic agents and drugs that modulate the metabolism of methotrexate 4
  • Metabolic salvage using leucovorin (folinic acid) 4
  • Close monitoring of serum methotrexate and creatinine concentrations 4, 5
  • Use of glucarpidase (carboxypeptidase-G2) to hydrolyze methotrexate into noncytotoxic metabolites 4