Effective removal of methotrexate by high-flux hemodialysis

Abstract

The purpose of the present study was to examine the clearance of methotrexate (MTX) by high-flux hemodialysis (HD) in pediatric oncology patients. We present three patients who experienced nephrotoxicity and prolonged exposure to toxic MTX concentrations following high-dose infusions during treatment for osteogenic sarcomas. Each patient was successfully treated with high-flux HD, followed by carboxypeptidase G2 (CPDG2) in two cases. Minimal systemic toxicity occurred. We review the literature and discuss guidelines for early and aggressive treatment for this complication of high-dose MTX therapy. Clinically important removal of MTX depends upon prompt initiation of HD after detection of nephrotoxicity and delayed clearance of MTX. Therapy is indicated in cases where compassionate use of CPDG(2) may not be available, or while awaiting its delivery.

High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

“…Rebound increases in MTX concentrations to levels approaching those that existed prior to institution of the dialysis-based method have been reported. The most effec- 24,25,28,70 Such methods of mechanical MTX removal, however, may not be available readily outside of major medical centers and include the risks associated with the insertion of vascular-access devices, the transfusion of blood products, electrolyte imbalances, and the risk of bleeding secondary to heparinization, thrombocytopenia, and anemia. 24,25,70,74 Compared with dialysis-based methods, the use of CPDG 2 is tolerated well and results in a more profound, rapid, and consistent decrease in plasma MTX concentrations, and rebounds Ͻ 10% in plasma MTX concentrations were observed in only 60% of patients who were treated with CPDG 2 .…”

“…The most effec- 24,25,28,70 Such methods of mechanical MTX removal, however, may not be available readily outside of major medical centers and include the risks associated with the insertion of vascular-access devices, the transfusion of blood products, electrolyte imbalances, and the risk of bleeding secondary to heparinization, thrombocytopenia, and anemia. 24,25,70,74 Compared with dialysis-based methods, the use of CPDG 2 is tolerated well and results in a more profound, rapid, and consistent decrease in plasma MTX concentrations, and rebounds Ͻ 10% in plasma MTX concentrations were observed in only 60% of patients who were treated with CPDG 2 . 34,35 A retrospective comparison of the recovery of renal function after supportive therapy that included dialysis versus CPDG 2 in patients with HDMTX-induced renal dysfunction is limited by the varying degrees of renal damage and the differing of definitions used in the literature to define renal recovery.…”

“…Only 3 patients had a decrease Ͼ 90% in MTX concentrations with the use of a single method in 1 dialysis session. 28,69,70 Increases in MTX plasma concentrations after the completion of dialysis-based methods were reported and quantified in seven reports. Rebound increases in postdialysis plasma MTX concentrations by 10 -221% of the postprocedure MTX levels 21,71,72 and to 90 -100% of the preprocedure MTX levels were reported.…”

“…Rebound increases in postdialysis plasma MTX concentrations by 10 -221% of the postprocedure MTX levels 21,71,72 and to 90 -100% of the preprocedure MTX levels were reported. 23,24,26,73 Reported complications from the various dialysis methods included cardiac arrest in one patient after plasma exchange, 23 bleeding from the catheter exit site, 24 anemia, 24,25 thrombocytopenia, 24,74 and hypokalemia and severe hypophosphatemia, 70 but the incidence of these complications could not be estimated accurately.…”

Drug-induced impairment of renal function

“…71,72 Newer potential therapies include carboxypeptidase G2 ([CPDG2] glucarpidase), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites. CPDG2 has been shown to efficiently reduce toxic MTX levels.…”