Could a patient with rheumatoid arthritis on methotrexate 20 mg weekly who now has acute kidney injury, pancytopenia, and fever be experiencing methotrexate toxicity, and what is the appropriate treatment?

Methotrexate Toxicity as Cause of AKI, Pancytopenia, and Fever

Yes, this presentation is highly consistent with methotrexate toxicity, and immediate treatment with leucovorin (folinic acid) is life-saving and must be initiated without delay. 1

Clinical Recognition

This triad of acute kidney injury, pancytopenia, and fever in a patient on methotrexate 20 mg weekly represents a medical emergency requiring immediate intervention. The presentation is classic for methotrexate-induced toxicity, particularly given that:

• Myelosuppression accounts for 67 out of 164 methotrexate-associated fatalities, making it the most lethal complication 1
• Renal insufficiency is the primary risk factor for toxicity due to impaired drug clearance (85% renal excretion), creating a vicious cycle where AKI leads to methotrexate accumulation, which worsens both renal function and bone marrow suppression 1, 2
• Fever in the setting of pancytopenia suggests neutropenic sepsis, a life-threatening complication requiring urgent intervention 1

Immediate Management Protocol

First-Line Antidote Therapy

Leucovorin (folinic acid) must be administered immediately upon suspicion of methotrexate toxicity, as efficacy diminishes dramatically after 24 hours and is doubtful if initiated >24 hours after last methotrexate dose 1:

• Initial dosing: 15 mg IV or PO every 6 hours until toxicity resolves 1
• For severe toxicity with unknown methotrexate levels: up to 100 mg/m² IV, followed by doses every 6 hours until methotrexate levels fall below 0.05 µmol/L 1
• Critical pitfall: Do NOT confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote 1

Supportive Care Measures

Aggressive IV hydration and urinary alkalinization with sodium bicarbonate should be initiated immediately to enhance renal elimination and prevent methotrexate precipitation in renal tubules 1, 3:

• Target urine pH >7.0 to prevent crystallization 3
• Monitor urine output and serum creatinine closely 3

Management of Neutropenic Fever

For severe neutropenia (<1×10⁹/L) with fever, broad-spectrum antibiotics must be initiated immediately, with consideration of filgrastim (G-CSF) 5 µg/kg subcutaneously daily to accelerate myeloid recovery 1, 4:

• Monitor for sepsis with high vigilance, as mortality risk is substantial 1
• Blood cultures should be obtained before antibiotic administration 4

Discontinuation of Methotrexate

Methotrexate must be held immediately and should remain discontinued until infection resolves, blood counts recover, and renal function improves 1, 2:

• If WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L, methotrexate should be withheld 1, 2

Risk Factors Present in This Case

Several factors likely contributed to this patient's toxicity:

• Acute kidney injury creating impaired methotrexate clearance and drug accumulation 2, 5
• Possible lack of adequate folate supplementation (should be 1-5 mg daily except on methotrexate day) 1, 6
• Potential drug interactions (NSAIDs, trimethoprim-sulfamethoxazole, PPIs, or penicillins reduce renal elimination) 1, 2
• Possible dosing error (accidental daily instead of weekly dosing) 1, 6

Monitoring During Treatment

Close monitoring of the following parameters is essential 1, 4:

• Complete blood count with differential every 24-48 hours until recovery 1
• Serum creatinine and urine output 3
• Serum methotrexate levels (if available) to guide leucovorin duration 3
• Signs of infection and sepsis 4

Expected Recovery Timeline

With appropriate leucovorin rescue therapy, bone marrow recovery typically begins within 7-10 days, though complete normalization may take several weeks 4:

• In one case report, blood counts showed improvement by day 7 and normalized within one month 4
• Recovery time depends on severity of toxicity, renal function, and promptness of leucovorin administration 1

Advanced Rescue Therapy

If plasma methotrexate levels remain elevated despite standard measures, glucarpidase (carboxypeptidase G2) should be obtained on a compassionate-use basis from the National Institutes of Health 1, 5:

• Licensed for treatment of high plasma MTX levels >1 µmol/L in patients with compromised renal function 5
• This is typically reserved for high-dose methotrexate toxicity but may be considered in severe cases 3

Prevention of Future Toxicity

If methotrexate is restarted after recovery 2:

• Reduce dose by 50% in setting of renal impairment (CrCl 20-50 mL/min) 2
• Ensure mandatory folic acid supplementation of at least 5 mg weekly (or 1 mg daily except on methotrexate day) 1, 2
• Enhanced monitoring schedule: CBC, LFTs, and renal function every 2-4 weeks initially 2
• Avoid nephrotoxic medications and drugs that interact with methotrexate 2
• Consider alternative disease-modifying agents (e.g., azathioprine) if toxicity recurs 2