How to manage methotrexate (MTX) toxicity in a patient with impaired renal function undergoing hemodialysis (HD)?

Management of Methotrexate Toxicity in Hemodialysis Patients

Methotrexate should be avoided entirely in patients on hemodialysis, but if toxicity occurs, immediate management includes discontinuing methotrexate, administering high-dose leucovorin rescue, aggressive alkalinized hydration, and considering extended hours high-flux hemodialysis with glucarpidase as rescue therapy. 1, 2, 3

Immediate Management Steps

Discontinue Methotrexate and Initiate Leucovorin Rescue

• Stop methotrexate immediately upon recognition of toxicity 1, 4
• Administer leucovorin (folinic acid) as the primary antidote for hematologic and other methotrexate toxicity 4, 3
• High-dose leucovorin can be used as sole therapy for severe methotrexate intoxication with tolerable morbidity, even with MTX levels >100 micromol/L at 24 hours 5
• Leucovorin dosing should be guided by serum methotrexate concentrations and continued until MTX levels fall below 0.05 micromolar (5 x 10⁻⁸ mol/L) 3

Aggressive Supportive Care

• Intensify alkalinized hydration immediately to prevent methotrexate precipitation in renal tubules, particularly critical when plasma creatinine increases 2, 6
• Maintain urine pH above 7.0 through sodium bicarbonate administration (oral or IV) 3, 6
• Administer IV fluids at 125 mL/m²/hr (3 liters/m²/day) during and for 2 days after methotrexate exposure 3

Hemodialysis Considerations

• Extended hours high-flux hemodialysis is the only dialysis modality proven effective for methotrexate clearance 3, 7
• Standard hemodialysis and peritoneal dialysis are generally ineffective for methotrexate elimination 3, 8
• High-flux dialysis with extended treatment duration (24+ hours) can reduce MTX concentrations from 390 micromol/L to 7 micromol/L 9
• Combined hemodialysis and charcoal hemoperfusion may provide additional benefit, achieving 73% reduction in methotrexate and preventing gastrointestinal and hematologic toxicity 9

Glucarpidase Rescue

• Glucarpidase is indicated for toxic methotrexate concentrations in patients with delayed clearance due to impaired renal function 3
• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 3
• Glucarpidase has been used successfully via both intravenous and intrathecal routes in overdose cases 3

Monitoring Requirements

Laboratory Monitoring

• Measure serum methotrexate levels at 24 hours post-exposure and at least daily until levels fall below 0.05 micromolar 3
• Monitor complete blood count, renal function (serum creatinine), and liver function tests every 2-4 weeks initially 1, 4
• Check for downward trends in blood counts even if absolute values remain within normal range 1
• Monitor urine output and perform urinalysis to detect early signs of kidney injury including hematuria, proteinuria, and crystalluria 1

Clinical Monitoring

• Watch for signs of methotrexate toxicity including mucositis, fever, diarrhea, skin reactions, and myelosuppression 1, 6
• Significant neutropenia (neutrophil count <1,000/μL) may occur and last 1-5 days 5
• Thrombocytopenia (platelet count <100,000/μL) may occur and last 5-10 days 5

Critical Pitfalls to Avoid

Contraindications and Dose Adjustments

• Patients with creatinine clearance <20 mL/min should avoid methotrexate entirely 2
• Even low-dose methotrexate can cause severe pancytopenia in end-stage renal disease patients on hemodialysis 8
• Myelosuppression is the most important cause of methotrexate-associated death and is significantly increased in renal dysfunction 1, 2

Drug Interactions

• Avoid trimethoprim-sulfamethoxazole, which inhibits folate utilization and can cause severe pancytopenia 1, 4
• Avoid NSAIDs, penicillins, and proton pump inhibitors that compete for renal tubular secretion and significantly increase methotrexate toxicity 1, 2
• These medications should be held during methotrexate therapy and for 1-2 weeks afterward 4

Monitoring Errors

• Do not rely on estimated GFR alone; calculate actual creatinine clearance using the Cockcroft-Gault equation 1, 2
• Do not perform liver function tests within 2 days after methotrexate dose, as transient elevations may occur 4
• Duration of exposure to elevated methotrexate levels is more toxic than peak levels alone 2, 3

Prevention for Future Courses

Folic Acid Supplementation

• Mandatory folic acid supplementation of 1-5 mg daily (except on methotrexate day) reduces hematologic, gastrointestinal, and hepatic toxicity without compromising efficacy 10, 1, 4

Alternative Therapies

• Consider azathioprine as an alternative disease-modifying agent, as it does not require dose adjustment in moderate renal impairment 1
• Anti-TNF alpha blockers can be considered as alternatives when methotrexate cannot be safely continued 8