What is the management approach for a patient with acute kidney injury (AKI) on hemodialysis (HD) who has received high-dose methotrexate for cancer treatment?

Management of AKI on Hemodialysis Following High-Dose Methotrexate

In patients with AKI on hemodialysis after high-dose methotrexate, immediately administer glucarpidase (if available) while continuing intensive hemodialysis with high-flux dialyzers or hemodiafiltration, maintain aggressive hydration with urinary alkalinization, and escalate leucovorin dosing based on methotrexate levels until concentrations fall below 0.05 micromolar. 1, 2, 3

Immediate Interventions

Glucarpidase Administration

• Administer glucarpidase as soon as possible when methotrexate levels remain elevated despite standard measures, as this enzyme rapidly hydrolyzes methotrexate to inactive metabolites and has demonstrated successful renal recovery even in anuric AKI. 1, 4, 2
• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for the enzyme and will be degraded. 1
• The typical dose is approximately 50 U/kg (range 13-65.6 U/kg). 5
• Critical caveat: Glucarpidase is expensive and may not be immediately available; if unavailable or delayed, proceed directly to intensive dialysis strategies. 3

Renal Replacement Therapy Strategy

• Perform daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions of at least 6 hours duration until methotrexate levels are sufficiently low for leucovorin neutralization. 3
• High-flux dialyzers are essential—standard hemodialysis and peritoneal dialysis are ineffective for methotrexate clearance. 1, 3
• Expect methotrexate elimination half-life during dialysis sessions of approximately 4-5 hours. 3
• Anticipate rebound: Serum methotrexate concentrations will rebound by approximately 40% after each dialysis session due to redistribution from tissue compartments, necessitating repeated daily sessions. 3
• Continue dialysis sessions until methotrexate levels remain below 0.05 micromolar (5 x 10⁻⁸ mol/L) between sessions. 1

Hydration and Alkalinization

• Maintain aggressive intravenous hydration at 125 mL/m²/hr (3 liters/m²/day) even while on dialysis. 1
• Alkalinize urine to maintain pH above 7.0 using sodium bicarbonate (oral or IV) to prevent methotrexate crystallization in renal tubules. 1, 2
• Monitor fluid status carefully to avoid volume overload, adjusting ultrafiltration goals during dialysis accordingly. 1

Leucovorin Rescue Escalation

• Escalate leucovorin dosing based on methotrexate levels: If methotrexate concentration is >10 micromolar at 24 hours, give leucovorin 100 mg/m² IV every 3 hours until levels fall below 1 micromolar, then 100 mg/m² IV every 6 hours until below 0.05 micromolar. 1
• If methotrexate levels exceed 50 micromolar at 24 hours or >5 micromolar at 48 hours, increase leucovorin to 150-200 mg/m² IV every 3 hours. 1
• Do not administer leucovorin intrathecally—this is a critical safety warning. 1
• Continue leucovorin for an additional 24 hours (total 14 doses over 84 hours) if significant toxicity develops. 1

Monitoring Requirements

Methotrexate Levels

• Measure serum methotrexate concentration at least daily (and ideally every 12 hours) until levels fall below 0.05 micromolar. 1
• Measure levels immediately before and after each dialysis session to assess clearance and rebound. 3

Renal Function and Electrolytes

• Monitor serum creatinine, BUN, and electrolytes at least daily. 1
• Assess fluid balance with strict intake/output monitoring. 6
• Monitor for hyperkalemia, metabolic acidosis, and uremic complications. 7

Hematologic Toxicity

• Check complete blood count with differential daily, as myelosuppression typically occurs 7-10 days after methotrexate administration. 1, 2
• If significant leukopenia or thrombocytopenia develops, temporarily discontinue methotrexate (if additional doses planned) and increase leucovorin. 1

Other Organ Toxicity

• Monitor for mucositis, stomatitis, hepatotoxicity (transaminases, bilirubin), and dermatologic toxicity. 2
• These toxicities worsen with prolonged methotrexate exposure, emphasizing the urgency of clearance. 2

Medication Management

Discontinue Nephrotoxic Agents

• Immediately discontinue all nephrotoxic medications including NSAIDs, ACE inhibitors, ARBs, diuretics, and other renally-excreted drugs. 6, 8
• Review all medications for potential drug interactions that impair methotrexate clearance or protein binding (probenecid, salicylates, sulfonamides, penicillins). 6

Dose Adjustment for Other Medications

• Adjust all renally-excreted medications based on severely reduced GFR. 6
• Consider using cystatin C-based estimates or direct GFR measurement for drugs with narrow therapeutic windows. 6

Expected Timeline and Prognosis

Renal Recovery

• Median time to complete methotrexate excretion with glucarpidase and intensive dialysis is approximately 355 hours (15 days) for the toxic course. 5
• Creatinine levels return to baseline in approximately 80% of cases within 1 month, with complete recovery in 3-6 weeks. 3, 5
• All patients in reported series eventually recovered renal function without permanent dialysis dependence. 4, 3, 5

Mortality Considerations

• While renal recovery is typical, patients who develop AKI after high-dose methotrexate have reduced overall survival (median 37 months vs 145 months without AKI), likely reflecting underlying disease severity. 9
• Death can occur from sepsis, septic shock, or aplastic anemia during the acute toxic phase. 1

Risk Factors That Led to This Complication

Understanding these factors helps prevent recurrence:

• LDH >380 units/L and albumin <3.6 g/dL are the strongest predictors of methotrexate-induced AKI (odds ratio ~4 for each). 9
• Baseline eGFR <112 mL/min, age >40 years, and higher Charlson comorbidity index also increase risk. 9
• Volume depletion, acidic urine, and concurrent nephrotoxic drugs at the time of methotrexate administration. 2

Resumption of High-Dose Methotrexate

If additional methotrexate courses are required for cancer treatment, resumption is possible after complete renal recovery:

• Wait until creatinine returns to baseline and eGFR >60 mL/min/1.73m². 6, 5
• Median time to next methotrexate course after glucarpidase use is typically several weeks. 5
• Upon rechallenge, methotrexate excretion normalizes (median 90 hours for next course vs 355 hours for toxic course), with only 1 in 13 patients experiencing repeat nephrotoxicity. 5
• Implement enhanced preventive measures: more aggressive hydration (start 12-24 hours before methotrexate), meticulous urinary alkalinization, and more frequent methotrexate level monitoring. 2, 5
• Cancer patients should not be denied necessary chemotherapy due to prior AKI, but require appropriate dose adjustment and enhanced monitoring. 6

Common Pitfalls to Avoid

• Delaying glucarpidase administration: Effectiveness decreases as time from methotrexate administration increases. 1, 2
• Using standard hemodialysis instead of high-flux dialyzers—this is ineffective for methotrexate clearance. 1, 3
• Stopping dialysis after one session due to improved methotrexate levels, without anticipating the 40% rebound phenomenon. 3
• Administering leucovorin immediately before or after glucarpidase, which inactivates the leucovorin. 1
• Continuing nephrotoxic medications during the recovery phase. 6, 8
• Inadequate urinary alkalinization, allowing continued methotrexate crystallization. 1, 2