What are the guidelines for adjusting Methotrexate (MTX) dose in patients with Acute Kidney Injury (AKI)?

From the Guidelines

Methotrexate dosing should be reduced in patients with acute kidney injury (AKI), with a reduction of 25% for mild AKI (GFR 60-80 ml/min), 50% for moderate AKI (GFR 30-59 ml/min), and consideration of withholding methotrexate until renal function improves for severe AKI (GFR <30 ml/min). According to the British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016 1, reduction in methotrexate dosage should be considered in those with suboptimal renal function < 20 mL min^-1. Additionally, the KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD recommends reducing the dose of methotrexate when GFR < 60 ml/min/1.73 m^2 and avoiding it if possible when GFR < 15 ml/min/1.73 m^2 1.

Key Considerations

• Close monitoring of methotrexate levels is essential if therapy must continue during AKI, with target levels depending on the indication.
• Patients should be well-hydrated and urine alkalinized (pH >7) using sodium bicarbonate to enhance methotrexate solubility and excretion.
• Leucovorin rescue may be needed at higher doses than usual to prevent toxicity.
• Methotrexate toxicity during AKI can manifest as myelosuppression, mucositis, and worsening kidney function, creating a dangerous cycle.

Monitoring and Management

• Daily monitoring of renal function, complete blood counts, and methotrexate levels is recommended until kidney function stabilizes.
• Folic acid supplementation is recommended to prevent toxicity 1.
• Regular monitoring of liver function tests and complete blood counts is essential to prevent hepatotoxicity and myelosuppression 1.

From the FDA Drug Label

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. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION

The methotrexate dose should be adjusted in patients with Acute Kidney Injury (AKI) to prevent toxicity.

• Monitoring of serum methotrexate levels is recommended to identify patients at high risk for methotrexate toxicity.
• Leucovorin dosing should be adjusted to reduce the risk of methotrexate toxicity in patients with impaired renal function 2. Key considerations for dose adjustment include:
• Renal function: impaired renal function can increase methotrexate serum levels
• Delayed drug clearance: can lead to prolonged exposure to the drug and increased risk of toxicity
• Pharmacokinetic monitoring: can help identify patients at high risk for methotrexate toxicity and guide adjustments to leucovorin dosing.

From the Research

Methotrexate Dose Adjustment in Acute Kidney Injury (AKI)

• Methotrexate (MTX) is a chemotherapeutic agent used to treat various types of cancer and autoimmune diseases, but its use can be complicated by AKI, a rare but life-threatening condition 3.
• AKI can lead to MTX overexposure, resulting in higher risks of extrakidney toxicities, morbidity, and mortality, as well as secondary chronic kidney disease (CKD) requiring reduced doses or contraindication of subsequent MTX infusions 3.
• The management of MTX-AKI involves preventive measures, including alkaline hyperhydration, withdrawal of nephrotoxic agents, metabolic salvage using leucovorin, and close monitoring of serum MTX and creatinine concentrations 3.
• Glucarpidase, a recombinant bacterial enzyme, can be used to hydrolyze MTX into noncytotoxic metabolites, preventing or lessening AKI and other potential toxicities 3.

Factors Influencing Methotrexate Dose Adjustment

• Patient-related factors, such as appropriate body weight, organ clearance, and serum protein concentration, can affect drug dosing in AKI patients 4.
• Drug-related factors, including molecular weight, protein binding, volume of distribution, hydrophilicity, and hydrophobicity, can also impact dosing 4.
• Renal replacement therapy (RRT)-related factors, such as type, modality of solute removal, filter characteristics, dose, and duration, can influence drug dosing in AKI patients on RRT 4.

Methotrexate-Related Toxicity in Renal Dysfunction

• Methotrexate-related toxicity can occur in patients with rheumatoid arthritis and renal dysfunction, with a toxicity rate of approximately 30% 5.
• Factors associated with MTX-related toxicity include hydroxychloroquine use, baseline estimated glomerular filtration rate (eGFR), and female sex 5.
• Hydroxychloroquine use has been shown to exhibit a protective effect against MTX-associated toxicity development 5.

General Principles of Drug Dosing in AKI

• Antibiotic dosing in critically ill patients with AKI often does not achieve pharmacodynamic goals, and concerns for toxicity associated with higher doses are real 6.
• The concept of dialysis "dose" is complex and has been extended to AKI, with urea kinetic modeling being the mainstay of dose quantification in end-stage renal disease 7.
• Extrapolation of these techniques to critically ill patients with AKI is difficult due to non-steady state conditions, alterations in total-body water, and changing renal excretory capacity 7.